bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒05‒01
fifty-five papers selected by
Viktor Korolchuk, Newcastle University
  1. Misfolded GBA/β-glucocerebrosidase impairs ER-quality control by chaperone-mediated autophagy in Parkinson disease.
  2. Mitochondrial quality control in health and in Parkinson's disease.
  3. Glutamine, MTOR and autophagy: a multiconnection relationship.
  4. Multifaceted roles of TAX1BP1 in autophagy.
  5. Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
  6. Autophagy guards tendon homeostasis.
  7. Targeting impaired autophagy as a therapeutic strategy for Koolen-de Vries syndrome.
  8. Hunting Out the autophagic problem in Huntington disease.
  9. Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
  10. Metabolism and autophagy in plants - A perfect match.
  11. The TORC1 phosphoproteome in C. elegans reveals roles in transcription and autophagy.
  12. Mutations in V-ATPase in follicular lymphoma activate autophagic flux creating a targetable dependency.
  13. Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage.
  14. Autophagy in age-related macular degeneration.
  15. Chemotactic cell migration: the core autophagy protein ATG9A is at the leading edge.
  16. Atg39 binding to the inner nuclear membrane triggers nuclear envelope deformation in piecemeal macronucleophagy.
  17. Dynein is required for Rab7-dependent endosome maturation, retrograde dendritic transport, and degradation.
  18. Increased LCN2 (lipocalin 2) in the RPE decreases autophagy and activates inflammasome-ferroptosis processes in a mouse model of dry AMD.
  19. Acetylation of SCFD1 regulates SNARE complex formation and autophagosome-lysosome fusion.
  20. Intrinsic role of chaperone-mediated autophagy in cancer stem cell maintenance.
  21. CROP: a retromer-PROPPIN complex mediating membrane fission in the endo-lysosomal system.
  22. Unlocking the gate to GABARAPL2.
  23. 4.8% sevoflurane induces activation of autophagy in human neuroblastoma SH-SY5Y cells by the AMPK/mTOR signaling pathway.
  24. The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases.
  25. Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function.
  26. Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes.
  27. [Role of autophagy in the maintenance of skeletal muscle mass].
  28. AMPK Signaling Regulates Mitophagy and Mitochondrial ATP Production in Human Trophoblast Cell Line BeWo.
  29. Overexpression of progranulin increases pathological protein accumulation by suppressing autophagic flux.
  30. The crosstalk between bacteria and host autophagy: host defense or bacteria offense.
  31. Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling.
  32. Manganese induces S-nitrosylation of PINK1 leading to nerve cell damage by repressing PINK1/Parkin-mediated mitophagy.
  33. Molecular interaction of stress granules with Tau and autophagy in Alzheimer's disease.
  34. Trifluridine induces HUVECs senescence by inhibiting mTOR-dependent autophagy.
  35. COPII vesicles in plant autophagy and endomembrane trafficking.
  36. Cumulative autophagy insufficiency in mice leads to progression of β-cell failure.
  37. Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function.
  38. Interphase chromosome condensation in nutrient-starved conditions requires Cdc14 and Hmo1, but not condensin, in yeast.
  39. Neuropathology of Multiple System Atrophy, a Glioneuronal Degenerative Disease.
  40. Correlation of Ferroptosis and Other Types of Cell Death in Neurodegenerative Diseases.
  41. Increased mTORC2 pathway activation in lymph nodes of iMCD-TAFRO.
  42. Epigenetic regulation of autophagy in coronavirus disease 2019 (COVID-19).
  43. Optineurin promotes myogenesis during muscle regeneration in mice by autophagic degradation of GSK3β.
  44. Neuronal mTOR Outposts: Implications for Translation, Signaling, and Plasticity.
  45. 2-Mercaptoethanol promotes porcine oocyte maturation in vitro by maintaining autophagy homeostasis.
  46. Golgi-Bypass Is a Major Unconventional Route for Translocation to the Plasma Membrane of Non-Apical Membrane Cargoes in Aspergillus nidulans.
  47. Endogenous hydrogen sulfide counteracts polystyrene nanoplastics-induced mitochondrial apoptosis and excessive autophagy via regulating Nrf2 and PGC-1α signaling pathway in mouse spermatocyte-derived GC-2spd(ts) cells.
  48. Rational engineering of biomimetic flavylium fluorophores for regulating the lysosomal and mitochondrial localization behavior by pH-induced structure switch and application to fluorescence imaging.
  49. MCC950 ameliorates the dementia symptom at the early age of line M83 mouse and reduces hippocampal α-synuclein accumulation.
  50. Targeted autophagy disruption reveals the central role of macrophage iron metabolism in systemic iron homeostasis.
  51. S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders.
  52. Apigenin alleviated PA-induced pyroptosis by activating autophagy in hepatocytes.
  53. Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway.
  54. A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients.
  55. Lysosome-targeting luminescent lanthanide complexes: from molecular design to bioimaging.
  1. Autophagy. 2022 Apr 28.
    Misfolded GBA/β-glucocerebrosidase impairs ER-quality control by chaperone-mediated autophagy in Parkinson disease.
    Sheng-Han Kuo, Inmaculada Tasset, Ana Maria Cuervo, David Sulzer.
      Inhibition of chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation for intracellular proteins, may contribute to pathogenesis in neurodegenerative diseases including Parkinson disease (PD). Pathogenic variants of PD-related proteins that reside in the cytosol, including SNCA/alpha-synuclein, LRRK2 (leucine rich repeat kinase 2), UCHL1 (ubiquitin Cterminal hydrolase 1) and VPS35 (VPS35 retromer complex component), exert inhibitory effects on CMA. Decreased CMA activity has also been reported in sporadic PD patients, consistent with an association between CMA inhibition and PD. We have now reported the first example of CMA dysfunction caused by a non-cytosolic PD-related protein, GBA/β-glucocerebrosidase, the most common genetic risk factor for PD, which uncovers a new role for CMA in endoplasmic reticulum (ER) quality control.
    Keywords:  Chaperones; ER quality control; lysosomal enzymes; lysosomes; neurodegeneration; protein aggregation; protein trafficking; proteotoxicity
    DOI:  https://doi.org/10.1080/15548627.2022.2071383
  2. Physiol Rev. 2022 Apr 25.
    Mitochondrial quality control in health and in Parkinson's disease.
    Mohamed A Eldeeb, Rhalena A Thomas, Mohamed A Ragheb, Armaan Fallahi, Edward A Fon.
      As a central hub for cellular metabolism and intracellular signalling, the mitochondrion is a pivotal organelle, dysfunction of which has been linked to several human diseases including neurodegenerative disorders, and in particular Parkinson's disease. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to monitor, identify, repair and/or eliminate abnormal or misfolded proteins within the mitochondrion and/or the dysfunctional mitochondrion itself. Chaperones identify unstable or otherwise abnormal conformations in mitochondrial proteins and can promote their refolding to recover their correct conformation and stability. However, if repair is not possible, the abnormal protein is selectively degraded to prevent potentially damaging interactions with other proteins or its oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of such abnormal or misfolded protein species. Mitophagy (a specific kind of autophagy) mediates the selective elimination of dysfunctional mitochondria, in order to prevent the deleterious effects the dysfunctional organelles within the cell. Despite our increasing understanding of the molecular responses toward dysfunctional mitochondria, many key aspects remain relatively poorly understood. Herein, we review the emerging mechanisms of mitochondrial quality control including quality control strategies coupled to mitochondrial import mechanisms. In addition, we review the molecular mechanisms regulating mitophagy with an emphasis on the regulation of PINK1/PARKIN-mediated mitophagy in cellular physiology and in the context of Parkinson's disease cell biology.
    Keywords:  PINK1/Parkin; Parkinson's disease; mitochondrial quality control; mitophagy; protein quality control
    DOI:  https://doi.org/10.1152/physrev.00041.2021
  3. Autophagy. 2022 Apr 26. 1-2
    Glutamine, MTOR and autophagy: a multiconnection relationship.
    Clément Bodineau, Mercedes Tomé, Piedad Del Socorro Murdoch, Raúl V Durán.
      Cancer cells metabolize glutamine mostly through glutaminolysis, a metabolic pathway that activates MTORC1. The AMPK-MTORC1 signaling axis is a key regulator of cell growth and proliferation. Our recent investigation identified that the connection between glutamine and AMPK is not restricted to glutaminolysis. Rather, we demonstrated the crucial role of ASNS (asparagine synthetase (glutamine-hydrolyzing)) and the GABA shunt for the metabolic control of the AMPK-MTORC1 axis during glutamine sufficiency. Our results elucidated a metabolic network by which glutamine metabolism regulates the MTORC1-macroautophagy/autophagy pathway through two independent branches involving glutaminolysis and ASNS-GABA shunt.
    Keywords:  ASNS; GABA-shunt; MTORC1; glutamine; glutamoptosis
    DOI:  https://doi.org/10.1080/15548627.2022.2062875
  4. Autophagy. 2022 Apr 26.
    Multifaceted roles of TAX1BP1 in autophagy.
    Jesse White, Sujit Suklabaidya, Mai Tram Vo, Young Bong Choi, Edward W Harhaj.
      TAX1BP1 is a selective macroautophagy/autophagy receptor that plays a central role in host defense to pathogens and in regulating the innate immune system. TAX1BP1 facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis and regulates TLR3 (toll-like receptor 3)-TLR4 and DDX58/RIG-I-like receptor (RLR) signaling by targeting TICAM1 and MAVS for autophagic degradation respectively. In addition to these canonical autophagy receptor functions, TAX1BP1 can also exert multiple accessory functions that influence the biogenesis and maturation of autophagosomes. In this review, we will discuss and integrate recent findings related to the autophagy function of TAX1BP1 and highlight outstanding questions regarding its functions in autophagy and regulation of innate immunity and host defense.
    Keywords:  Aggrephagy; TAX1BP1; autophagy; host defense; innate immune signaling; xenophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2070331
  5. Autophagy. 2022 Apr 26.
    Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
    Angelika B Harbauer, Thomas L Schwarz.
      Mitostasis, the process of mitochondrial maintenance by biogenesis and degradative mechanisms, is challenged by the extreme length of axons. PINK1 (PTEN induced putative kinase 1) is a mitochondrial protein that targets damaged mitochondria for mitophagy. In reconciling the short half-life of PINK1 with the need for mitophagy of damaged axonal mitochondria, we found that axonal mitophagy depends on local translation of the Pink1 mRNA. Using live-cell imaging, we detected co-transport of the Pink1 mRNA on mitochondria in neurons, which is crucial for mitophagy in distal parts of the cell. Here we discuss how the coupling of the transcript of a short-lived mitochondrial protein to the movement of its target organelles contributes to our understanding of mitostasis in neurons.
    Keywords:  Axonal biology; RNA transport; local translation; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2070332
  6. Cell Death Dis. 2022 Apr 23. 13(4): 402
    Autophagy guards tendon homeostasis.
    Costanza Montagna, Rene B Svensson, Monika L Bayer, Salvatore Rizza, Emiliano Maiani, Ching-Yan Chloé Yeung, Giuseppe Filomeni, Michael Kjær.
      Tendons are vital collagen-dense specialized connective tissues transducing the force from skeletal muscle to the bone, thus enabling movement of the human body. Tendon cells adjust matrix turnover in response to physiological tissue loading and pathological overloading (tendinopathy). Nevertheless, the regulation of tendon matrix quality control is still poorly understood and the pathogenesis of tendinopathy is presently unsolved. Autophagy, the major mechanism of degradation and recycling of cellular components, plays a fundamental role in the homeostasis of several tissues. Here, we investigate the contribution of autophagy to human tendons' physiology, and we provide in vivo evidence that it is an active process in human tendon tissue. We show that selective autophagy of the endoplasmic reticulum (ER-phagy), regulates the secretion of type I procollagen (PC1), the major component of tendon extracellular matrix. Pharmacological activation of autophagy by inhibition of mTOR pathway alters the ultrastructural morphology of three-dimensional tissue-engineered tendons, shifting collagen fibrils size distribution. Moreover, autophagy induction negatively affects the biomechanical properties of the tissue-engineered tendons, causing a reduction in mechanical strength under tensile force. Overall, our results provide the first evidence that autophagy regulates tendon homeostasis by controlling PC1 quality control, thus potentially playing a role in the development of injured tendons.
    DOI:  https://doi.org/10.1038/s41419-022-04824-7
  7. Autophagy. 2022 Apr 29. 1-3
    Targeting impaired autophagy as a therapeutic strategy for Koolen-de Vries syndrome.
    Ting Li, Ailing Li, Xin Pan.
      Koolen-de Vries syndrome (KdVS) is a genomic disorder characterized by intellectual disability, heart failure, hypotonia and congenital malformations, which is caused by haploinsufficiency of KANSL1. Because the pathogenesis of the disease is unknown, there is still no effective treatment. Here, we discuss our recent work identifying KANSL1 as an essential gene for macroautophagy/autophagy. We find that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation by transcriptionally regulating Stx17 expression. Kansl1 heterozygous mice exhibit impaired neuronal and cardiac functions, resulting from the obstruction of autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species in these tissues. Furthermore, we discovered an FDA-approved drug, 13-cis retinoic acid, is capable of alleviating these mitophagic defects and neurobehavioral abnormalities in Kansl1 heterozygous mice by promoting autophagosome-lysosome fusion via directly binding to STX17 and SNAP29. Our study provides the proof of concept to set up a link between KANSL1, autophagic defects and KdVS, and also proposes a therapeutic strategy for treatment of KdVS.
    Keywords:  13-cis retinoic acid; KANSL1; STX17; autophagy; koolen-de Vries syndrome; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2022.2069904
  8. Autophagy. 2022 Apr 25.
    Hunting Out the autophagic problem in Huntington disease.
    Karolina Pircs, Roger A Barker, Johan Jakobsson.
      Huntington disease is an inherited, progressive, incurable neurodegenerative disorder that primarily affects cells in the brain. Although the genetic basis for this condition has been known for nearly 30 years, how this causes disease is still unresolved. Of late there has been increasing evidence suggesting that dysfunction in macroautophagic/autophagic pathways may contribute to cellular dysfunction and death. In our recent work we highlight more precisely how and where this problem might arise in this pathway using directly reprogrammed neurons.
    Keywords:  Autophagy; CRISPR; Huntington disease; induced neurons; lentiviral vector; macroautophagy; neurodegenerative diseases; reprogramming
    DOI:  https://doi.org/10.1080/15548627.2022.2069438
  9. Autophagy. 2022 Apr 25.
    Essential role of lysosomal Ca2+-mediated TFEB activation in mitophagy and functional adaptation of pancreatic β-cells to metabolic stress.
    Kihyoun Park, Myung-Shik Lee.
      Although the role of pancreatic β-cell macroautophagy/autophagy is well known, that of β-cell mitophagy is unclear. We investigated the changes of lysosomal Ca2+ by mitochondrial or metabolic stress that can modulate TFEB activation and, additionally, the role of TFEB-induced mitophagy in β-cell function. Mitochondrial or metabolic stress induces mitophagy, which is mediated by lysosomal Ca2+ release, increased cytosolic [Ca2+] and subsequent TFEB activation. Lysosomal Ca2+ release is replenished by ER→lysosome Ca2+ refilling through ER Ca2+ exit channels, which is important for the increase of cytosolic [Ca2+] and mitophagy by mitochondria stressors. High-fat diet (HFD) feeding augments pancreatic β-cell mitophagy, probably as an adaptation to metabolic stress. HFD-induced increase of β-cell mitophagy is reduced by tfeb KO, leading to increased ROS and decreased mitochondrial complex activity or oxygen consumption in tfeb-KO islets. In tfeb Δβ-cell mice, HFD-induced glucose intolerance and β-cell dysfunction are aggravated. Expression of mitophagy receptor genes including Optn or Calcoco2 is increased by mitochondrial or metabolic stressors in a TFEB-dependent manner, likely contributing to increased mitophagy. These results suggest that lysosomal Ca2+ release in conjunction with ER→lysosome Ca2+ refilling is important for TFEB activation and mitophagy induction, which contributes to pancreatic β-cell adaptation to metabolic stress.
    Keywords:  Ca2+; TFEB; lysosome; mitophagy; pancreatic β-cells
    DOI:  https://doi.org/10.1080/15548627.2022.2069956
  10. FEBS Lett. 2022 Apr 25.
    Metabolism and autophagy in plants - A perfect match.
    Sahar Magen, Heike Seybold, Daniel Laloum, Tamar Avin-Wittenberg.
      Autophagy is a eukaryotic cellular transport mechanism that delivers intracellular macromolecules, proteins, and even organelles to a lytic organelle (vacuole in yeast and plants/lysosome in animals) for degradation and nutrient recycling. The process is mediated by highly conserved Autophagy-Related (ATG) proteins. In plants, autophagy maintains cellular homeostasis under favorable conditions, guaranteeing normal plant growth and fitness. Severe stress such as nutrient starvation and plant senescence further induce it, thus ensuring plant survival under unfavorable conditions by providing nutrients through the removal of damaged or aged proteins, or organelles. In this article, we examine the interplay between metabolism and autophagy, focusing on the different aspects of this reciprocal relationship. We show that autophagy has a strong influence on a range of metabolic processes, whereas, at the same time, even single metabolites can activate autophagy. We highlight the involvement of ATG genes in metabolism, examine the role of the macronutrients carbon and nitrogen, as well as various micronutrients, and take a closer look at how the interaction between autophagy and metabolism impacts on plant phenotypes and yield.
    Keywords:  ATG genes; Arabidopsis; Autophagy; Carbon; Crops; Metabolism; Micronutrients; Nitrogen; Plant; Yield
    DOI:  https://doi.org/10.1002/1873-3468.14359
  11. iScience. 2022 May 20. 25(5): 104186
    The TORC1 phosphoproteome in C. elegans reveals roles in transcription and autophagy.
    Aileen K Sewell, Zachary C Poss, Christopher C Ebmeier, Jeremy R Jacobsen, William M Old, Min Han.
      The protein kinase complex target of rapamycin complex 1 (TORC1) is a critical mediator of nutrient sensing that has been widely studied in cultured cells and yeast, yet our understanding of the regulatory activities of TORC1 in the context of a whole, multi-cellular organism is still very limited. Using Caenorhabditis elegans, we analyzed the DAF-15/Raptor-dependent phosphoproteome by quantitative mass spectrometry and characterized direct kinase targets by in vitro kinase assays. Here, we show new targets of TORC1 that indicate previously unknown regulation of transcription and autophagy. Our results further show that DAF-15/Raptor is differentially expressed during postembryonic development, suggesting a dynamic role for TORC1 signaling throughout the life span. This study provides a comprehensive view of the TORC1 phosphoproteome, reveals more than 100 DAF-15/Raptor-dependent phosphosites that reflect the complex function of TORC1 in a whole, multi-cellular organism, and serves as a rich resource to the field.
    Keywords:  Cell biology; Developmental biology; Functional aspects of cell biology; Omics; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104186
  12. Autophagy. 2022 Apr 28.
    Mutations in V-ATPase in follicular lymphoma activate autophagic flux creating a targetable dependency.
    Fangyang Wang, Ying Yang, Daniel J Klionsky, Sami N Malek.
      The recent discovery of recurrent gene mutations in chaperones or components of the vacuolar-type H+-translocating ATPase (V-ATPase) in follicular lymphoma (FL) was an unexpected finding. The application of whole exome sequencing and targeted gene re-sequencing has resulted in the identification of mutations in ATP6AP1, ATP6V1B2 and VMA21 in a combined 30% of FL, together constituting a major novel mutated pathway in this disease. Interestingly, no other human hematological malignancy carries these mutations at more than sporadic occurrences, implicating unique aspects of FL biology requiring these mutations. The mutations in ATP6V1B2 and VMA21 through separate mechanisms impair lysosomal V-ATPase activity resulting in an elevated lysosomal pH. The elevated lysosomal pH impairs protein and peptide hydrolysis and associates with reduced cytoplasmic amino acid concentrations resulting in compensatory activation of autophagic flux. The elevated autophagic flux constitutes a survival dependency for FL cells and can be targeted with inhibitors to ULK1 and multiple recently identified cyclin dependent kinase inhibitors. Targeting autophagy alone or in combination with other targeted therapies constitutes a novel therapeutic opportunity for FL patients.
    Keywords:  Autophagy; cancer; disease; therapeutics; tumor
    DOI:  https://doi.org/10.1080/15548627.2022.2071382
  13. Autophagy. 2022 Apr 26. 1-17
    Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage.
    Yuhua Zhang, Qiaojun Fang, Hongfeng Wang, Jieyu Qi, Shan Sun, Menghui Liao, Yunhao Wu, Yangnan Hu, Pei Jiang, Cheng Cheng, Xiaoyun Qian, Mingliang Tang, Wei Cao, Shang Xiang, Chen Zhang, Jianming Yang, Xia Gao, Zheng Ying, Renjie Chai.
      Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.
    Keywords:  ATF3; PRKN-PINK1; cell apoptosis; hair cells; kinetin; mitophagy; neomycin
    DOI:  https://doi.org/10.1080/15548627.2022.2062872
  14. Autophagy. 2022 Apr 25.
    Autophagy in age-related macular degeneration.
    Kai Kaarniranta, Janusz Blasiak, Paloma Liton, Michael Boulton, Daniel J Klionsky, Debasish Sinha.
      Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with limited understanding of its pathogenesis and a lack of effective treatment. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to geographic atrophy and/or choroidal neovascularization and fibrosis. The role of macroautophagy/autophagy in AMD pathology is steadily emerging. This review describes selective and secretory autophagy and their role in drusen biogenesis, senescence-associated secretory phenotype, inflammation and epithelial-mesenchymal transition in the pathogenesis of AMD.
    Keywords:  autophagy; immune response; lysosome; retina; stress; vision
    DOI:  https://doi.org/10.1080/15548627.2022.2069437
  15. Autophagy. 2022 Apr 29. 1-3
    Chemotactic cell migration: the core autophagy protein ATG9A is at the leading edge.
    Daniele Campisi, Laurence Desrues, Kleouforo-Paul Dembélé, Alexandre Mutel, Renaud Parment, Pierrick Gandolfo, Hélène Castel, Fabrice Morin.
      Accumulating data indicate that several components of the macroautophagy/autophagy machinery mediate additional functions, which do not depend on autophagosome biogenesis or lysosomal cargo degradation. In this context, we found that the core autophagy protein ATG9A participates in the chemotactic movement of several cell lines, including highly invasive glioblastoma cells. Accordingly, ATG9A-depleted cells are unable to form large and persistent leading-edge protrusions. By the design of an ATG9A-pHluorin construct and TIRF imaging, we established that ATG9A-positive vesicles are targeted toward the migration front, where their exocytosis is synchronized with protrusive activity. We finally demonstrated that ATG9A, through its interaction with clathrin adaptor complexes, controls the delivery of ITGB1 (integrin subunit beta 1) to the migration front and normal adhesion dynamics. Together, our work indicates that ATG9A protein has a wider role than anticipated and constitutes a critical component of vesicular trafficking allowing the expansion of cell protrusions and their anchorage to the extracellular matrix.
    Keywords:  ATG9A; autophagy; cell adhesion; chemotactic migration; exocytosis
    DOI:  https://doi.org/10.1080/15548627.2022.2069903
  16. Autophagy. 2022 Apr 29. 1-2
    Atg39 binding to the inner nuclear membrane triggers nuclear envelope deformation in piecemeal macronucleophagy.
    Keisuke Mochida, Hitoshi Nakatogawa.
      Recent studies have revealed that even the nucleus can be degraded by selective macroautophagy (hereafter macronucleophagy). In Saccharomyces cerevisiae, the nuclear envelope (NE) protein Atg39 acts as a macronucleophagy receptor that mediates sequestration of nucleus-derived double-membrane vesicles (NDVs) into phagophores. The outer and inner membranes of these NDVs are derived from the outer and inner nuclear membranes (ONM and INM), respectively, and the lumen contains nucleoplasmic material. Little was known about the mechanisms underlying macronucleophagy, including how the two nuclear membranes are coordinately deformed to generate NDVs and what nuclear components are preferentially loaded into or rather eliminated from NDVs. We found that Atg39 links the ONM and INM through the ONM-embedded transmembrane domain and INM-associated amphipathic helices (APHs). These APHs are important for Atg39 anchoring to the NE and autophagosome formation-coupled Atg39 clustering in the NE. In addition, the overaccumulation of Atg39 in the NE caused NE protrusion toward the cytoplasm depending on the APHs. These results allowed us to propose the mechanism by which Atg39 conducts NDV formation in coordination with autophagosome formation during macronucleophagy.
    Keywords:  Atg39; autophagy receptor; macroautophagy; nucleophagy; nucleus; yeast
    DOI:  https://doi.org/10.1080/15548627.2022.2069957
  17. J Neurosci. 2022 Apr 26. pii: JN-RM-2530-21. [Epub ahead of print]
    Dynein is required for Rab7-dependent endosome maturation, retrograde dendritic transport, and degradation.
    Chan Choo Yap, Laura Digilio, Lloyd P McMahon, Tuanlao Wang, Bettina Winckler.
      In all cell types, endocytosed cargo is transported along a set of endosomal compartments, which are linked maturationally from early endosomes (EE) via late endosomes (LE) to lysosomes. Lysosomes are critical for degradation of proteins that enter through endocytic as well as autophagic pathways. Rab7 is the master regulator of early-to-late endosome maturation, motility, and fusion with lysosomes. We previously showed that most degradative lysosomes are localized in the soma and in the first 25 µm of the dendrite and that bulk degradation of dendritic membrane proteins occurs in/near the soma. Dendritic late endosomes therefore move retrogradely in a Rab7-dependent manner for fusion with somatic lysosomes. We now used cultured E18 rat hippocampal neurons of both sexes to determine which microtubule motor is responsible for degradative flux of late endosomes. Based on multiple approaches (inhibiting dynein/dynactin itself or inhibiting dynein recruitment to endosomes by expressing the C-terminus of the Rab7 effector, RILP), we now demonstrate that net retrograde flux of late endosomes in dendrites is supported by dynein. Inhibition of dynein also delays maturation of somatic endosomes, as evidenced by excessive accumulation of Rab7. In addition, degradation of dendritic cargos is inhibited. Our results also suggest that GDP-GTP cycling of Rab7 appears necessary not only for endosomal maturation but also for fusion with lysosomes subsequent to arrival in the soma. In conclusion, Rab7-dependent dynein/dynactin recruitment to dendritic endosomes plays multifaceted roles in dendritic endosome maturation as well as retrograde transport of late endosomes to sustain normal degradative flux.Significance StatementLysosomes are critical for degradation of membrane and extracellular proteins that enter through endocytosis. Lysosomes are also the endpoint of autophagy and thus responsible for protein and organelle homeostasis. Endosomal-lysosomal dysfunction is linked to neurodegeneration and aging. We identify roles in dendrites for two proteins with links to human diseases, Rab7 and dynein. Our previous work identified a process that requires directional retrograde transport in dendrites, namely efficient degradation of short-lived membrane proteins. Based on multiple approaches, we demonstrate that Rab7-dependent recruitment of dynein motors supports net retrograde transport to lysosomes and is needed for endosome maturation. Our data also suggest that GDP-GTP cycling of Rab7 is required for fusion with lysosomes and degradation, subsequent to arrival in the soma.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2530-21.2022
  18. Autophagy. 2022 Apr 26. 1-20
    Increased LCN2 (lipocalin 2) in the RPE decreases autophagy and activates inflammasome-ferroptosis processes in a mouse model of dry AMD.
    Urvi Gupta, Sayan Ghosh, Callen T Wallace, Peng Shang, Ying Xin, Archana Padmanabhan Nair, Meysam Yazdankhah, Anastasia Strizhakova, Mark A Ross, Haitao Liu, Stacey Hose, Nadezda A Stepicheva, Olivia Chowdhury, Mihir Nemani, Vishnu Maddipatla, Rhonda Grebe, Manjula Das, Kira L Lathrop, José-Alain Sahel, J Samuel Zigler, Jiang Qian, Arkasubhra Ghosh, Yuri Sergeev, James T Handa, Claudette M St Croix, Debasish Sinha.
      In dry age-related macular degeneration (AMD), LCN2 (lipocalin 2) is upregulated. Whereas LCN2 has been implicated in AMD pathogenesis, the mechanism remains unknown. Here, we report that in retinal pigmented epithelial (RPE) cells, LCN2 regulates macroautophagy/autophagy, in addition to maintaining iron homeostasis. LCN2 binds to ATG4B to form an LCN2-ATG4B-LC3-II complex, thereby regulating ATG4B activity and LC3-II lipidation. Thus, increased LCN2 reduced autophagy flux. Moreover, RPE cells from cryba1 KO, as well as sting1 KO and Sting1Gt mutant mice (models with abnormal iron chelation), showed decreased autophagy flux and increased LCN2, indicative of CGAS- and STING1-mediated inflammasome activation. Live cell imaging of RPE cells with elevated LCN2 also showed a correlation between inflammasome activation and increased fluorescence intensity of the Liperfluo dye, indicative of oxidative stress-induced ferroptosis. Interestingly, both in human AMD patients and in mouse models with a dry AMD-like phenotype (cryba1 cKO and KO), the LCN2 homodimer variant is increased significantly compared to the monomer. Sub-retinal injection of the LCN2 homodimer secreted by RPE cells into NOD-SCID mice leads to retinal degeneration. In addition, we generated an LCN2 monoclonal antibody that neutralizes both the monomer and homodimer variants and rescued autophagy and ferroptosis activities in cryba1 cKO mice. Furthermore, the antibody rescued retinal function in cryba1 cKO mice as assessed by electroretinography. Here, we identify a molecular pathway whereby increased LCN2 elicits pathophysiology in the RPE, cells known to drive dry AMD pathology, thus providing a possible therapeutic strategy for a disease with no current treatment options.Abbreviations: ACTB: actin, beta; Ad-GFP: adenovirus-green fluorescent protein; Ad-LCN2: adenovirus-lipocalin 2; Ad-LCN2-GFP: adenovirus-LCN2-green fluorescent protein; LCN2AKT2: AKT serine/threonine kinase 2; AMBRA1: autophagy and beclin 1 regulator 1; AMD: age-related macular degeneration; ARPE19: adult retinal pigment epithelial cell line-19; Asp278: aspartate 278; ATG4B: autophagy related 4B cysteine peptidase; ATG4C: autophagy related 4C cysteine peptidase; ATG7: autophagy related 7; ATG9B: autophagy related 9B; BLOC-1: biogenesis of lysosomal organelles complex 1; BLOC1S1: biogenesis of lysosomal organelles complex 1 subunit 1; C57BL/6J: C57 black 6J; CGAS: cyclic GMP-AMP synthase; ChQ: chloroquine; cKO: conditional knockout; Cys74: cysteine 74; Dab2: DAB adaptor protein 2; Def: deferoxamine; DHE: dihydroethidium; DMSO: dimethyl sulfoxide; ERG: electroretinography; FAC: ferric ammonium citrate; Fe2+: ferrous; FTH1: ferritin heavy chain 1; GPX: glutathione peroxidase; GST: glutathione S-transferase; H2O2: hydrogen peroxide; His280: histidine 280; IFNL/IFNλ: interferon lambda; IL1B/IL-1β: interleukin 1 beta; IS: Inner segment; ITGB1/integrin β1: integrin subunit beta 1; KO: knockout; LC3-GST: microtubule associated protein 1 light chain 3-GST; C-terminal fusion; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LCN2: lipocalin 2; mAb: monoclonal antibody; MDA: malondialdehyde; MMP9: matrix metallopeptidase 9; NLRP3: NLR family pyrin domain containing 3; NOD-SCID: nonobese diabetic-severe combined immunodeficiency; OS: outer segment; PBS: phosphate-buffered saline; PMEL/PMEL17: premelanosome protein; RFP: red fluorescent protein; rLCN2: recombinant LCN2; ROS: reactive oxygen species; RPE SM: retinal pigmented epithelium spent medium; RPE: retinal pigment epithelium; RSL3: RAS-selective lethal; scRNAseq: single-cell ribonucleic acid sequencing; SD-OCT: spectral domain optical coherence tomography; shRNA: small hairpin ribonucleic acid; SM: spent medium; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TYR: tyrosinase; VCL: vinculin; WT: wild type.
    Keywords:  ATG4B; autophagy; dry age-related macular degeneration; ferroptosis; inflammasome; iron; lipocalin 2; monoclonal/neutralizing antibody; oxidative stress; retinal pigmented epithelial cells
    DOI:  https://doi.org/10.1080/15548627.2022.2062887
  19. Autophagy. 2022 Apr 24. 1-15
    Acetylation of SCFD1 regulates SNARE complex formation and autophagosome-lysosome fusion.
    Hong Huang, Qinqin Ouyang, Kunrong Mei, Ting Liu, Qiming Sun, Wei Liu, Rong Liu.
      SCFD1 (sec1 family domain containing 1) was recently shown to function in autophagosome-lysosome fusion, and multiple studies have demonstrated the regulatory impacts of acetylation (a post-translational modification) on macroautophagy/autophagy. Here, we demonstrate that both acetylation- and phosphorylation-dependent mechanisms control SCFD1's function in autophagosome-lysosome fusion. After detecting a decrease in the extent of SCFD1 acetylation under autophagy-stimulated conditions, we found that KAT2B/PCAF catalyzes the acetylation of residues K126 and K515 of SCFD1; we also showed that these two residues are deacetylated by SIRT4. Importantly, we showed that AMPK-controlled SCFD1 phosphorylation strongly disrupts the capacity of SCFD1 to interact with KAT2B, thus ensuring that the SCFD1 acetylation level remains low. Finally, we demonstrated that SCFD1 acetylation inhibits autophagic flux, specifically by blocking STX17-SNAP29-VAMP8 SNARE complex formation. Thus, our study reveals a mechanism through which phosphorylation and acetylation modifications of SCFD1 mediate SNARE complex formation to regulate autophagosome maturation.ACLY: ATP citrate lyase; CREB: cAMP responsive element binding protein; EBSS: nutrient-deprivation medium; EP300: E1A binding protein p300; KAT5/TIP60: lysine acetyltransferase 5; HOPS: homotypic fusion and protein sorting; MS: mass spectroscopy; SCFD1: sec1 family domain containing 1; SM: Sec1/Munc18; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; UVRAG: UV radiation resistance associated.
    Keywords:  Autophagosome; SCFD1; SNARE; autophagy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2022.2064624
  20. Autophagy. 2022 Apr 27. 1-2
    Intrinsic role of chaperone-mediated autophagy in cancer stem cell maintenance.
    Jaione Auzmendi-Iriarte, Ander Matheu.
      Chaperone-mediated autophagy (CMA) is a selective type of autophagy specialized in the individual degradation of targeted proteins. Its impact in any cancer stem cell (CSC) subtype remained elusive. In a recent study, we characterized the expression of LAMP2A and CMA activity in glioblastoma revealing its enrichment in a glioma stem cell (GSC) subpopulation. LAMP2A downregulation diminishes proliferation and self-renewal and induces apoptosis in GSCs in vitro, whereas it delays tumor progression in vivo. The underlying molecular signature of CMA comprises several proteomic and transcriptomic pathways with special relevance to mitochondrial function, the interferon pathway and extracellular matrix interactions. Remarkably, these activities are translated into the clinical scenario, as glioblastoma (GBM) samples show increased expression of LAMP2 compared to healthy tissue, with this expression being positively associated with malignancy grade, TMZ resistance and lower patient survival. These results reveal a novel function of CMA as an intrinsic regulator of GSC tumorigenic properties and highlight its relevance in GBM progression.
    Keywords:  CMA; Cancer stem cell; LAMP2A; glioblastoma; proteomic and transcriptomic analysis
    DOI:  https://doi.org/10.1080/15548627.2022.2069450
  21. EMBO J. 2022 Apr 25. e109646
    CROP: a retromer-PROPPIN complex mediating membrane fission in the endo-lysosomal system.
    Thibault Courtellemont, Maria Giovanna De Leo, Navin Gopaldass, Andreas Mayer.
      Endo-lysosomal compartments exchange proteins by fusing, fissioning, and through endosomal transport carriers. Thereby, they sort many plasma membrane receptors and transporters and control cellular signaling and metabolism. How the membrane fission events are catalyzed is poorly understood. Here, we identify the novel CROP complex as a factor acting at this step. CROP joins members of two protein families: the peripheral subunits of retromer, a coat forming endosomal transport carriers, and membrane inserting PROPPINs. Integration into CROP potentiates the membrane fission activity of the PROPPIN Atg18 on synthetic liposomes and confers strong preference for binding PI(3,5)P2 , a phosphoinositide required for membrane fission activity. Disrupting CROP blocks fragmentation of lysosome-like yeast vacuoles in vivo. CROP-deficient mammalian endosomes accumulate micrometer-long tubules and fail to export cargo, suggesting that carriers attempt to form but cannot separate from these organelles. PROPPINs compete for retromer binding with the SNX-BAR proteins, which recruit retromer to the membrane during the formation of endosomal carriers. Transition from retromer-SNX-BAR complexes to retromer-PROPPIN complexes might hence switch retromer activities from cargo capture to membrane fission.
    Keywords:  autophagy; endosomes; lysosomes; retromer; yeast
    DOI:  https://doi.org/10.15252/embj.2021109646
  22. Biol Futur. 2022 Apr 29.
    Unlocking the gate to GABARAPL2.
    Jennifer C Y Chan, Sharon M Gorski.
      GABARAPL2 was initially characterized for its involvement in protein transport and membrane fusion events, but has since gained notoriety for its role in autophagy. GABARAPL2 is frequently studied alongside its GABARAP subfamily members, GABARAP and GABARAPL1. Although functional redundancy exists among the subfamily members, a complex network of molecular interactions, physiological processes and pathologies can be primarily related to GABARAPL2. GABARAPL2 has a multifaceted role, ranging from cellular differentiation to intracellular degradation. Much of what we know about GABARAPL2 is gained through identifying its interacting partners-a list that is constantly growing. In this article, we review both the autophagy-dependent and autophagy-independent roles of GABARAPL2, and emphasize their implications for both health and disease.
    Keywords:  Atg8; Autophagy; GABARAPL2; GATE-16
    DOI:  https://doi.org/10.1007/s42977-022-00119-2
  23. Neurotoxicology. 2022 Apr 23. pii: S0161-813X(22)00056-0. [Epub ahead of print]
    4.8% sevoflurane induces activation of autophagy in human neuroblastoma SH-SY5Y cells by the AMPK/mTOR signaling pathway.
    Jingjing Lv, Hao Cheng, Weidong Yao, Can Liu, Yongquan Chen, Xiaoju Jin, Zeyong Yang, Yuanhai Li.
      Prolonged sevoflurane exposure leads to neurotoxicity. Autophagy plays an important role in promoting cell survival in different conditions. However, the role and mechanism of autophagy in sevoflurane-induced neurotoxicity were not fully elucidated. We attempted to indicate whether sevoflurane could activate the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)-mediated autophagy to attenuate anesthetics-induced neuronal injury in this study. Sevoflurane treatment significantly decreased the cell viability and induced apoptosis of SH-SY5Y cells. The expression level of Bcl-2 decreased, while that of Bax remarkably increased. Meanwhile, autophagy was activated by sevoflurane exposure as evidenced by increased expression levels of autophagy-related proteins (LC3-II and Atg5), decreased expression level of autophagic substrate P62, and increased autophagosomes and autolysosomes. Further autophagosomes and fewer autolysosomes were observed in the presence of Bafilomycin A1, an autolysosomes degradation inhibitor, suggesting that sevoflurane induced autophagic flux rather than inhibiting degradation of autophagy. Activation of autophagy by rapamycin partly reversed the sevoflurane-decreased cell viability. In contrast, inhibition of autophagy by 3-Methyladenine (3-MA) or Atg5-targeted small interfering RNA (siRNA) aggravated the sevoflurane-induced neurotoxicity. Further examination revealed that sevoflurane-induced autophagy was mediated by the AMPK/mTOR signaling pathway, with increased p-AMPK expression and decreased p-mTOR expression. Collectively, these results indicated that sevoflurane activates autophagy by regulating the AMPK/mTOR signaling pathway, which is protective against sevoflurane-induced damage in SH-SY5Y cells. Our results may assist clinicians to develop further promising therapeutic strategies for the neurotoxicity induced by inhaled anesthetics.
    Keywords:  AMPK/mTOR signaling pathway; Apoptosis; Autophagy; SH-SY5Y cells; Sevoflurane
    DOI:  https://doi.org/10.1016/j.neuro.2022.04.008
  24. Biol Rev Camb Philos Soc. 2022 Apr 26.
    The PERKs of mitochondria protection during stress: insights for PERK modulation in neurodegenerative and metabolic diseases.
    Liliana M Almeida, Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.
      Protein kinase RNA-like ER kinase (PERK) is an endoplasmic reticulum (ER) stress sensor that responds to the accumulation of misfolded proteins. Once activated, PERK initiates signalling pathways that halt general protein production, increase the efficiency of ER quality control, and maintain redox homeostasis. PERK activation also protects mitochondrial homeostasis during stress. The location of PERK at the contact sites between the ER and the mitochondria creates a PERK-mitochondria axis that allows PERK to detect stress in both organelles, adapt their functions and prevent apoptosis. During ER stress, PERK activation triggers mitochondrial hyperfusion, preventing premature apoptotic fragmentation of the mitochondria. PERK activation also increases the formation of mitochondrial cristae and the assembly of respiratory supercomplexes, enhancing cellular ATP-generating capacity. PERK strengthens mitochondrial quality control during stress by promoting the expression of mitochondrial chaperones and proteases and by increasing mitochondrial biogenesis and mitophagy, resulting in renewal of the mitochondrial network. But how does PERK mediate all these changes in mitochondrial homeostasis? In addition to the classic PERK-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway, PERK can activate other protective pathways - PERK-O-linked N-acetyl-glucosamine transferase (OGT), PERK-transcription factor EB (TFEB), and PERK-nuclear factor erythroid 2-related factor 2 (NRF2) - contributing to broader regulation of mitochondrial dynamics, metabolism, and quality control. The pharmacological activation of PERK is protective in models of neurodegenerative and metabolic diseases, such as Huntington's disease, progressive supranuclear palsy and obesity, while the inhibition of PERK was protective in models of Parkinson's and prion diseases and diabetes. In this review, we address the molecular mechanisms by which PERK regulates mitochondrial dynamics, metabolism and quality control, and discuss the therapeutic potential of targeting PERK in neurodegenerative and metabolic diseases.
    Keywords:  PERK; dynamics; endoplasmic reticulum; metabolic diseases; metabolism; mitochondria; neurodegeneration; stress; unfolded protein response
    DOI:  https://doi.org/10.1111/brv.12860
  25. Sci Rep. 2022 Apr 23. 12(1): 6674
    Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function.
    Fumie Mitani, Jianyu Lin, Tatsuya Sakamoto, Ryo Uehara, Tomoya Hikita, Takuya Yoshida, Andi Setiawan, Masayoshi Arai, Chitose Oneyama.
      Cancer cells secrete aberrantly large amounts of extracellular vesicles (EVs) including exosomes, which originate from multivesicular bodies (MVBs). Because EVs potentially contribute to tumor progression, EV inhibitors are of interest as novel therapeutics. We screened a fungal natural product library. Using cancer cells engineered to secrete luciferase-labeled EVs, we identified asteltoxin, which inhibits mitochondrial ATP synthase, as an EV inhibitor. Low concentrations of asteltoxin inhibited EV secretion without inducing mitochondrial damage. Asteltoxin attenuated cellular ATP levels and induced AMPK-mediated mTORC1 inactivation. Consequently, MiT/TFE transcription factors are translocated into the nucleus, promoting transcription of lysosomal genes and lysosome activation. Electron microscopy analysis revealed that the number of lysosomes increased relative to that of MVBs and the level of EVs decreased after treatment with asteltoxin or rapamycin, an mTORC1 inhibitor. These findings suggest that asteltoxin represents a new type of EV inhibitor that controls MVB fate.
    DOI:  https://doi.org/10.1038/s41598-022-10692-0
  26. J Nutr Biochem. 2022 Apr 21. pii: S0955-2863(22)00088-2. [Epub ahead of print] 109017
    Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes.
    Masashi Masuda, Risa Yoshida-Shimizu, Yuki Mori, Kohta Ohnishi, Yuichiro Adachi, Maiko Sakai, Serina Kabutoya, Hirokazu Ohminami, Hisami Yamanaka-Okumura, Hironori Yamamoto, Makoto Miyazaki, Yutaka Taketani.
      Lipophagy, a form of selective autophagy, degrades lipid droplet (LD) in adipose tissue and the liver. The chemotherapeutic isothiocyanate sulforaphane (SFN) contributes to lipolysis through the activation of hormone-sensitive lipase and the browning of white adipocytes. However, the details concerning the regulation of lipolysis in adipocytes by SFN-mediated autophagy remain unclear. In this study, we investigated the effects of SFN on autophagy in the epididymal fat of mice fed a high-fat diet (HFD) or control-fat diet (CFD) and on the molecular mechanisms of autophagy in differentiated 3T3-L1 cells. Western blotting revealed that the protein expression of lipidated LC3 (LC3-II), an autophagic substrate, was induced after 3T3-L1 adipocytes treatment with SFN. In addition, SFN increased the LC3-II protein expression in the epididymal fat of mice fed an HFD. Immunofluorescence showed that the SFN-induced LC3 expression was co-localized with LDs in 3T3-L1 adipocytes and with perilipin, the most abundant adipocyte-specific protein, in adipocytes of mice fed an HFD. Next, we confirmed that SFN activates autophagy flux in differentiated 3T3-L1 cells using the mCherry-EGFP-LC3 and GFP-LC3-RFP-LC3DG probe. Furthermore, we examined the induction mechanisms of autophagy by SFN in 3T3-L1 adipocytes using western blotting. ATG5 knockdown partially blocked the SFN-induced release of fatty acids from LDs in mature 3T3-L1 adipocytes. SFN time-dependently elicited the phosphorylation of AMPK, the dephosphorylation of mTOR, and the phosphorylation of ULK1 in differentiated 3T3-L1 cells. Taken together, these results suggest that SFN may provoke lipophagy through AMPK-mTOR-ULK1 pathway signaling, resulting in partial lipolysis of adipocytes. (246/250 words).
    Keywords:  Lipid droplets; adipose; autophagy; cell biology; dietary factors; obesity
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109017
  27. Zhongguo Gu Shang. 2022 Apr 25. 35(4): 374-8
    [Role of autophagy in the maintenance of skeletal muscle mass].
    A-Ying Liu, Quan-Bing Zhang, Yun Zhou, Feng Wang.
      As an important exercise and energy metabolism organ of the human body, the normal maintenance of skeletal muscle mass is essential for the body to perform normal physiological functions. The autophagy-lysosome (AL) pathway is a physiological or pathological mechanism that is ubiquitous in normal and diseased cells. It plays a key role in the maintaining of protein balance, removing damaged organelles, and the stability of internal environment. The smooth progress of the autophagy process needs to go through multiple steps, which are completed under the coordinated action of multiple factors. Autophagy maintains the muscle homeostasis of a healthy body by removing cell components such as damaged myofibrils and isolated cytoplasmic proteins. Autophagy could also provide the initial energy required for cell proliferation, promote muscle regeneration and remodeling after injury. At the same time, autophagy disorder is also an important cause of age-related skeletal muscle atrophy. Autophagy could affect the response of skeletal muscle to exercise, and increasing the level of basic autophagy is beneficial to improve the adaptive response of skeletal muscle to exercise. This article summarizes the role and pathways of autophagy in the maintenance of skeletal muscle quality, in order to provide effective rehabilitation strategies for clinical prevention and treatment of muscle atrophy.
    Keywords:  Autophagy; Lysosome; Muscular atrophy; Skeletal muscle
    DOI:  https://doi.org/10.12200/j.issn.1003-0034.2022.04.015
  28. Front Biosci (Landmark Ed). 2022 Apr 01. 27(4): 118
    AMPK Signaling Regulates Mitophagy and Mitochondrial ATP Production in Human Trophoblast Cell Line BeWo.
    Bin Wu, Yun Chen, Robert Clarke, Emmanuel Akala, Peixin Yang, Bin He, Haijun Gao.
      INTRODUCTION: Accumulating evidence suggests that mitochondrial structural and functional defects are present in human placentas affected by pregnancy related disorders, but mitophagy pathways in human trophoblast cells/placental tissues have not been investigated.METHODS: In this study, we investigated three major mitophagy pathways mediated by PRKN, FUNDC1, and BNIP3/BNIP3L in response to AMPK activation by AICAR and knockdown of PRKAA1/2 (AKD) in human trophoblast cell line BeWo and the effect of AKD on mitochondrial membrane potential and ATP production.
    RESULTS: Autophagy flux assay demonstrated that AMPK signaling activation stimulates autophagy, evidenced increased LC3II and SQSTM1 protein abundance in the whole cell lysates and mitochondrial fractions, and mitophagy flux assay demonstrated that the activation of AMPK signaling stimulates mitophagy via PRKN and FUNDC1 mediated but not BNIP3/BNIP3L mediated pathways. The stimulatory regulation of AMPK signaling on mitophagy was confirmed by AKD which reduced the abundance of LC3II, SQSTM1, PRKN, and FUNDC1 proteins, but increased the abundance of BNIP3/BNIP3L proteins. Coincidently, AKD resulted in elevated mitochondrial membrane potential and reduced mitochondrial ATP production, compared to control BeWo cells.
    CONCLUSIONS: In summary, AMPK signaling stimulates mitophagy in human trophoblast cells via PRKN and FUNDC1 mediated mitophagy pathways and AMPK regulated mitophagy contributes to the maintenance of mitochondrial membrane potential and mitochondrial ATP production.
    Keywords:  AMPK; ATP production; BeWo; human; mitochondria; mitophagy; trophoblast
    DOI:  https://doi.org/10.31083/j.fbl2704118
  29. Biochem Biophys Res Commun. 2022 Apr 16. pii: S0006-291X(22)00593-9. [Epub ahead of print]611 78-84
    Overexpression of progranulin increases pathological protein accumulation by suppressing autophagic flux.
    Yoshinori Tanaka, Shun-Ya Kusumoto, Yuki Honma, Kosuke Takeya, Masumi Eto.
      Progranulin (PGRN) haploinsufficiency from autosomal dominant mutations in the PGRN gene causes frontotemporal lobar degeneration, which is characterized by cytoplasmic inclusions predominantly containing TDP-43 (FTLD-TDP). PGRN supplementation for patients with a PGRN gene mutation has recently been proposed as a therapeutic strategy to suppress FTLD-TDP. However, it currently remains unclear whether excessive amounts of PGRN are beneficial or harmful. We herein report the effects of PGRN overexpression on autophagic flux in a cultured cell model. PGRN overexpression increased the level of an autophagosome marker without promoting autophagosome formation and decreased the signal intensity of an autolysosome marker, indicating the suppression of autophagic flux due to reductions in the formation of autolysosomes. Assessments of lysosome numbers and biogenesis using LysoTracker and cells stably expressing TFEB-GFP, respectively, indicated that PGRN overexpression increased the lysosome numbers without lysosomal biogenesis. These results suggest that PGRN overexpression suppressed autophagic flux by inhibiting autophagosome-lysosome fusion. Moreover, PGRN overexpression enhanced polyglutamine aggregation and aggregate-prone TDP-43 accumulation, indicating that the suppression of autophagic flux by excessive amounts of PGRN worsens the pathology of neurodegenerative diseases.
    Keywords:  Autophagic flux; Lysosome biogenesis; Progranulin; TDP-43
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.064
  30. J Microbiol. 2022 May;60(5): 451-460
    The crosstalk between bacteria and host autophagy: host defense or bacteria offense.
    Lin Zheng, Fang Wei, Guolin Li.
      Xenophagy is a specific selective autophagy for the elimination of intracellular bacteria. Current evidence suggests that the processes for host autophagy system to recognize and eliminate invading bacteria are complex, and vary according to different pathogens. Although both ubiquitin-dependent and ubiquitin-independent autophagy exist in host to defense invading bacteria, successful pathogens have evolved diverse strategies to escape from or paralyze host autophagy system. In this review, we discuss the mechanisms of host autophagy system to recognize and eliminate intracellular pathogens and the mechanisms of different pathogens to escape from or paralyze host autophagy system, with a particular focus on the most extensively studied bacteria.
    Keywords:  autophagy; bacteria; bacterial effector; infection; xenophagy
    DOI:  https://doi.org/10.1007/s12275-022-2009-z
  31. mBio. 2022 Apr 25. e0297421
    Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling.
    Emily J Strong, Jia Wang, Tony W Ng, Steven A Porcelli, Sunhee Lee.
      Autophagy is an ubiquitous homeostatic pathway in mammalian cells and plays a significant role in host immunity. Substantial evidence indicates that the ability of Mycobacterium tuberculosis (Mtb) to successfully evade immune responses is partially due to inhibition of autophagic pathways. Our previous screening of Mtb transposon mutants identified the PPE51 protein as an important autophagy-inhibiting effector. We found that expression of PPE51, either by infecting bacteria or by direct expression in host cells, suppressed responses to potent autophagy-inducing stimuli and interfered with bacterial phagocytosis. This phenotype was associated with reduced activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a key component of signaling pathways that stimulate autophagy. Multiple lines of evidence demonstrated that the effects of PPE51 are attributable to signal blocking by Toll-like receptor 2 (TLR2), a receptor with known involvement of activation of ERK1/2 and autophagy. Consistent with these results, mice with intact TLR2 signaling showed striking virulence attenuation for an Mtb ppe51 deletion mutant (Δ51) compared to wild-type Mtb, whereas infection of TLR2-deficient mice showed no such attenuation. Mice infected with Δ51 also displayed increased T cell responses to Mtb antigens and increased autophagy in infected lung tissues. Together, these results suggest that TLR2 activates relevant host immune functions during mycobacterial infection, which Mtb then evades through suppression of TLR2 signaling by PPE51. In addition to its previously identified function transporting substrates across the bacterial cell wall, our results demonstrate a direct role of PPE51 for evasion of both innate and adaptive immunity to Mtb. IMPORTANCE Tuberculosis is a significant global infectious disease caused by infection of the lungs with Mycobacterium tuberculosis, which resides and replicates mainly within host phagocytic cells. During coevolution with humans, Mtb has acquired various mechanisms to inhibit host cellular processes, including autophagy. Autophagy is a complex host cellular process that helps control intracellular infections by enhancing innate and adaptive immune responses. We identified the Mtb protein PPE51 as a mycobacterial effector that inhibits autophagy. We discovered TLR2 and mitogen-activated protein kinase signaling as the axis by which PPE51 mediates this effect. Autophagy regulation by PPE51, along with suppression of other TLR2-activated host cell functions, leads to increased bacterial survival in phagocytic cells and tissues of infected mice. A better understanding of how Mtb regulates autophagy and other host immune effectors could facilitate the design of new therapeutics or vaccines against tuberculosis.
    Keywords:  Mycobacterium tuberculosis; Toll-like receptor 2; autophagy; host-microbe interaction; innate immunity; mitogen-activated protein kinase ERK1/2
    DOI:  https://doi.org/10.1128/mbio.02974-21
  32. Sci Total Environ. 2022 Apr 20. pii: S0048-9697(22)02451-2. [Epub ahead of print] 155358
    Manganese induces S-nitrosylation of PINK1 leading to nerve cell damage by repressing PINK1/Parkin-mediated mitophagy.
    Kuan Liu, Zhiqi Liu, Zhuofan Liu, Zhuo Ma, Yu Deng, Wei Liu, Bin Xu.
      Chronic exposure to excess manganese (Mn) causes neurotoxicity, which is characterized by Parkinson-like symptoms and referred to as manganism. In the last few decades, mitochondrial damage and subsequent energy failure have been reported to be important mechanisms of Mn toxicity, yet how Mn causes mitochondrial damage remains largely unknown. Here, we demonstrated that Mn induced S-nitrosation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a master regulator in the mitophagy pathway, results in dysregulation of mitophagy and nerve cell injury in the rat striatum. We cultured primary neurons and used 1400 W, a potent and selective inducible nitric oxide synthase (iNOS) inhibitor, as an intervention to verify the precise mechanism of Mn-induced dysregulation of mitophagy. We demonstrated that Mn-induced S-nitrosylation of PINK1 decreased the phosphorylated level of parkin RBR E3 ubiquitin-protein ligase (Parkin), as well as the translocation of Parkin to damaged mitochondria, which led to the accumulation of damaged mitochondria and mitochondrial-mediated apoptosis. Our findings indicated the unusual connection between nitrative stress and mitochondrial dysfunction in Mn-induced neurotoxicity. These data highlight the role of S-nitrosation of PINK1 in Mn-induced dysregulation of mitophagy and provide a reliable target for the development of specific drugs and the early treatment of manganism, which has important theoretical and practical significance.
    Keywords:  Autophagy; Mitochondria damage; Mn; Neurotoxicity; Nitrosative stress
    DOI:  https://doi.org/10.1016/j.scitotenv.2022.155358
  33. Neurochem Int. 2022 Apr 21. pii: S0197-0186(22)00067-5. [Epub ahead of print] 105342
    Molecular interaction of stress granules with Tau and autophagy in Alzheimer's disease.
    Qin-Yuan Yu, Ling-Qi Ye, Hong-Lei Li.
      Stress Granules (SGs) are RNA granules composed of untranslated mRNA and associated proteins, which are related to the cytoplasmic metabolism of mRNA in response to cellular stress and certain drug stimuli. Physiological SGs are dynamic structures that protect cells from the effects of stress, and continuous stress ripens the SGs into more stable complexes. Numerous studies have found that dysregulation of RNA metabolism in stress response led to misfolded protein aggregation in the pathophysiology of neurodegenerative diseases. For example, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD), SGs aggregation is mainly due to up-regulation of SGs formation and down-regulation of SGs clearance. Recent studies have revealed the role of SGs in the pathogenesis and pathology of AD, especially the interaction of SGs and RNA-binding proteins with Tau and autophagy. Aggregation of SGs and increased RNA-binding proteins, especially TIA1, can facilitate Tau misfolding and propagation, and vice versa. Autophagy dysfunction disrupts the normal pathway of SGs clearance. In this review, we summarized the regulation of SGs and their relationship with Tau protein and autophagy, as well as the pathological mechanisms of AD such as RNA splicing, microglial cell proliferation and phagocytosis.
    Keywords:  Alzheimer's disease; Autophagy; RNA binding Protein; Stress granules; Tau
    DOI:  https://doi.org/10.1016/j.neuint.2022.105342
  34. Biochem Biophys Res Commun. 2022 Apr 15. pii: S0006-291X(22)00592-7. [Epub ahead of print]610 119-126
    Trifluridine induces HUVECs senescence by inhibiting mTOR-dependent autophagy.
    Hui-Jie Jia, Min Zhou, Manoj Kumar Vashisth, Jing Xia, Hui Hua, Qian-Long Dai, Shi-Rui Bai, Qi Zhao, Xiao-Bo Wang, Yi-Ling Shi.
      Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer. Chemotherapy is important for cancer treatment, but its adverse effects limit its use. Long-term side-effects caused by the drug used during chemotherapy are closely related to the accumulation of cellular senescence. However, the relationship between trifluridine and normal cell aging remains unclear. The purpose of this study is to evaluate whether trifluridine can induce the senescence of human umbilical vein endothelial cells and to explore the possible mechanism. Human umbilical vein endothelial cells were treated with trifluridine, senescence levels were measured via senescence-related acidic β-galactosidase staining and senescence-associated secretory phenotype levels respectively. Autophagy was assessed by the protein levels of LC3II/LC3I and p62, and LC3 fusion was detected by fluorescence microscopy. Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway. Trifluridine increased the expression of senescence-associated acidic β-galactosidase and senescence-related secretory phenotype mRNA levels in cells. In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.
    Keywords:  Autophagy; Senescence; Trifluridine; mTOR
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.063
  35. FEBS Lett. 2022 Apr 29.
    COPII vesicles in plant autophagy and endomembrane trafficking.
    Baiying Li, Yonglun Zeng, Liwen Jiang.
      In eukaryotes, the endomembrane system allows for spatiotemporal compartmentation of complicated cellular processes. The plant endomembrane system consists of the endoplasmic reticulum (ER), the Golgi apparatus (GA), the trans-Golgi network (TGN), the multivesicular body (MVB), and the vacuole. Anterograde traffic from the ER to GA is mediated by coat protein complex II (COPII) vesicles. Autophagy, an evolutionarily conserved catabolic process that turns over cellular materials upon nutrient deprivation or in adverse environments, exploits double-membrane autophagosomes to recycle unwanted constituents in the lysosome/vacuole. Accumulating evidence reveals novel functions of plant COPII vesicles in autophagy and their regulation by abiotic stresses. Here, we summarize current knowledge about plant COPII vesicles in the endomembrane trafficking and then highlight recent findings showing their distinct roles in modulating the autophagic flux and stress responses.
    Keywords:  COPII vesicle; autophagy; endomembrane trafficking; stress response
    DOI:  https://doi.org/10.1002/1873-3468.14362
  36. Biochem Biophys Res Commun. 2022 Apr 17. pii: S0006-291X(22)00563-0. [Epub ahead of print]611 38-45
    Cumulative autophagy insufficiency in mice leads to progression of β-cell failure.
    Luka Suzuki, Takeshi Miyatsuka, Miwa Himuro, Yuka Wakabayashi, Sho Osonoi, Masaki Miura, Takehiro Katahira, Yoshio Fujitani, Hitoshi Iida, Hiroki Mizukami, Yuya Nishida, Hirotaka Watada.
      Autophagy is known to play a pivotal role in β-cell function. While the lifelong inhibition of autophagy through Atg7 deletion in β cells has been demonstrated to lead to impaired glucose tolerance together with β-cell dysfunction, the temporal association between autophagy inhibition and β-cell dysfunction remains unclear. To address such questions, inducible β-cell-specific Atg7-knockout (iβAtg7KO) mice were generated, and autophagy inhibition was induced for two different time durations. Whereas 2 weeks of Atg7 ablation was sufficient to induce autophagy deficiency, confirmed by the accumulation of p62, iβAtg7KO mice exhibited normal glucose tolerance. In contrast, prolonged autophagy deficiency for 6 weeks resulted in glucose intolerance together with impaired insulin secretion. Direct mRNA sequencing and pathway analysis revealed that the gene set associated with insulin secretion was downregulated only after the 6-week prolonged autophagy inhibition. Furthermore, we identified a novel gene, Sprr1a, which was expressed at more than 50-fold higher levels during both the 2-week and 6-week autophagy inhibition. These findings suggest that autophagy insufficiency cumulatively leads to β-cell failure after a certain interval, accompanied by stepwise alterations of gene expression patterns.
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.040
  37. Sci Adv. 2022 Apr 29. 8(17): eabj5716
    Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function.
    Pearl P Y Lie, Lang Yoo, Chris N Goulbourne, Martin J Berg, Philip Stavrides, Chunfeng Huo, Ju-Hyun Lee, Ralph A Nixon.
      Dysfunction and mistrafficking of organelles in autophagy- and endosomal-lysosomal pathways are implicated in neurodegenerative diseases. Here, we reveal selective vulnerability of maturing degradative organelles (late endosomes/amphisomes) to disease-relevant local calcium dysregulation. These organelles undergo exclusive retrograde transport in axons, with occasional pauses triggered by regulated calcium efflux from agonist-evoked transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) channels-an effect greatly exaggerated by exogenous agonist mucolipin synthetic agonist 1 (ML-SA1). Deacidification of degradative organelles, as seen after Presenilin 1 (PSEN1) loss of function, induced pathological constitutive "inside-out" TRPML1 hyperactivation, slowing their transport comparably to ML-SA1 and causing accumulation in dystrophic axons. The mechanism involved calcium-mediated c-Jun N-terminal kinase (JNK) activation, which hyperphosphorylated dynein intermediate chain (DIC), reducing dynein activity. Blocking TRPML1 activation, JNK activity, or DIC1B serine-80 phosphorylation reversed transport deficits in PSEN1 knockout neurons. Our results, including features demonstrated in Alzheimer-mutant PSEN1 knockin mice, define a mechanism linking dysfunction and mistrafficking in lysosomal pathways to neuritic dystrophy under neurodegenerative conditions.
    DOI:  https://doi.org/10.1126/sciadv.abj5716
  38. Biochem Biophys Res Commun. 2022 Apr 20. pii: S0006-291X(22)00607-6. [Epub ahead of print]611 46-52
    Interphase chromosome condensation in nutrient-starved conditions requires Cdc14 and Hmo1, but not condensin, in yeast.
    Yuri Takeichi, Tsuneyuki Takuma, Kotaro Ohara, Most Naoshia Tasnin, Takashi Ushimaru.
      When asynchronously growing cells suffer from nutrient depletion and inactivation of target of rapamycin complex 1 (TORC1) protein kinase, the rDNA (rRNA gene) region is condensed in budding yeast Saccharomyces cerevisiae, which is executed by condensin and Cdc14 protein phosphatase. However, it is unknown whether these mitotic factors can condense the rDNA region in nutrient-starved interphase cells. Here, we show that condensin is not involved in TORC1 inactivation-induced rDNA condensation in G1 cells. Instead, the high-mobility group protein Hmo1 drove this process. The histone deacetylase Rpd3 and Cdc14, which repress rRNA transcription, were both required for the interphase rDNA condensation. Furthermore, interphase rDNA condensation necessitated CLIP and cohibin that tether rDNA to inner nuclear membranes. Finally, we showed that Hmo1, CLIP, Rpd3, and Cdc14 were required for survival in nutrient-starved G1 cells. Thus, this study disclosed novel features of interphase chromosome condensation.
    Keywords:  Cdc14; Condensin; Hmo1; Interphase chromosome condensation; Ribosomal DNA (rDNA); Target of rapamycin complex 1 (TORC1)
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.078
  39. Cerebellum. 2022 Apr 26.
    Neuropathology of Multiple System Atrophy, a Glioneuronal Degenerative Disease.
    Koichi Wakabayashi, Yasuo Miki, Kunikazu Tanji, Fumiaki Mori.
      Multiple system atrophy (MSA) is a fatal disease characterized pathologically by the widespread occurrence of aggregated α-synuclein in the oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). α-Synuclein aggregates are also found in the oligodendroglial nuclei and neuronal cytoplasm and nuclei. It is uncertain whether the primary source of α-synuclein in GCIs is originated from neurons or oligodendrocytes. Accumulating evidence suggests that there are two degenerative processes in this disease. One possibility is that numerous GCIs are associated with the impairment of oligo-myelin-axon-neuron complex, and the other is that neuronal inclusion pathology is also a primary event from the early stage. Both oligodendrocytes and neurons may be primarily affected in MSA, and the damage of one cell type contributes to the degeneration of the other. Vesicle-mediated transport plays a key role in the nuclear translocation of α-synuclein as well as in the formation of glial and neuronal α-synuclein inclusions. Recent studies have shown that impairment of autophagy can occur along with or as a result of α-synuclein accumulation in the brain of MSA and Lewy body disease. Activated autophagy may be implicated in the therapeutic approach for α-synucleinopathies.
    Keywords:  Autophagy; Glial cytoplasmic inclusion; Multi-system degeneration; Neuronal cytoplasmic inclusion; Vesicle-mediated transport; α-Synuclein
    DOI:  https://doi.org/10.1007/s12311-022-01407-2
  40. Neurosci Bull. 2022 Apr 28.
    Correlation of Ferroptosis and Other Types of Cell Death in Neurodegenerative Diseases.
    Xiaoting Dang, Xuejie Huan, Xixun Du, Xi Chen, Mingxia Bi, Chunling Yan, Qian Jiao, Hong Jiang.
      Ferroptosis is defined as an iron-dependent, non-apoptotic cell death pathway, with specific morphological phenotypes and biochemical changes. There is a growing realization that ferroptosis has significant implications for several neurodegenerative diseases. Even though ferroptosis is different from other forms of programmed death such as apoptosis and autophagic death, they involve a number of common protein molecules. This review focuses on current research on ferroptosis and summarizes the cross-talk among ferroptosis, apoptosis, and autophagy that are implicated in neurodegenerative diseases. We hope that this information provides new ideas for understanding the mechanisms and searching for potential therapeutic approaches and prevention of neurodegenerative diseases.
    Keywords:  Apoptosis; Autophagic death; Ferroptosis; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12264-022-00861-6
  41. J Cell Mol Med. 2022 Apr 30.
    Increased mTORC2 pathway activation in lymph nodes of iMCD-TAFRO.
    Alexis D Phillips, Joseph J Kakkis, Patricia Y Tsao, Sheila K Pierson, David C Fajgenbaum.
      Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening haematologic disorder involving polyclonal lymphoproliferation and organ dysfunction due to excessive cytokine production, including interleukin-6 (IL-6). Clinical trial and real-world data demonstrate that IL-6 inhibition is effective in 34-50% of patients. mTOR, which functions through mTORC1 and mTORC2, is a recently discovered therapeutic target. The mTOR inhibitor sirolimus, which preferentially inhibits mTORC1, has led to sustained remission in a small cohort of anti-IL-6-refractory iMCD patients with thrombocytopenia, anasarca, fever, renal dysfunction and organomegaly (iMCD-TAFRO). However, sirolimus has not shown uniform effect, potentially due to its limited mTORC2 inhibition. To investigate mTORC2 activation in iMCD, we quantified the mTORC2 effector protein pNDRG1 by immunohistochemistry of lymph node tissue from six iMCD-TAFRO and eight iMCD patients who do not meet TAFRO criteria (iMCD-not-otherwise-specified; iMCD-NOS). mTORC2 activation was increased in all regions of iMCD-TAFRO lymph nodes and the interfollicular space of iMCD-NOS compared with control tissue. Immunohistochemistry also revealed increased pNDRG1 expression in iMCD-TAFRO germinal centres compared with autoimmune lymphoproliferative syndrome (ALPS), an mTOR-driven, sirolimus-responsive lymphoproliferative disorder, and comparable staining between iMCD-NOS and ALPS. These results suggest increased mTORC2 activity in iMCD and that dual mTORC1/mTORC2 inhibitors may be a rational therapeutic approach.
    Keywords:  Castleman disease; TAFRO; autoimmune lymphoproliferative syndrome; iMCD; idiopathic multicentric Castleman disease; mTOR; mTORC2; pNDRG1
    DOI:  https://doi.org/10.1111/jcmm.17251
  42. Biochem Biophys Rep. 2022 Jul;30 101264
    Epigenetic regulation of autophagy in coronavirus disease 2019 (COVID-19).
    Hamid Behrouj, Omid Vakili, Adel Sadeghdoust, Neda Aligolighasemabadi, Parnian Khalili, Mozhdeh Zamani, Pooneh Mokarram.
      The coronavirus disease 2019 (COVID-19) pandemic has become the most serious global public health issue in the past two years, requiring effective therapeutic strategies. This viral infection is a contagious disease caused by new coronaviruses (nCoVs), also called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autophagy, as a highly conserved catabolic recycling process, plays a significant role in the growth and replication of coronaviruses (CoVs). Therefore, there is great interest in understanding the mechanisms that underlie autophagy modulation. The modulation of autophagy is a very complex and multifactorial process, which includes different epigenetic alterations, such as histone modifications and DNA methylation. These mechanisms are also known to be involved in SARS-CoV-2 replication. Thus, molecular understanding of the epigenetic pathways linked with autophagy and COVID-19, could provide novel therapeutic targets for COVID-19 eradication. In this context, the current review highlights the role of epigenetic regulation of autophagy in controlling COVID-19, focusing on the potential therapeutic implications.
    Keywords:  Autophagy; COVID-19; DNA methylation; Epigenetics; Histone modification
    DOI:  https://doi.org/10.1016/j.bbrep.2022.101264
  43. PLoS Biol. 2022 Apr 27. 20(4): e3001619
    Optineurin promotes myogenesis during muscle regeneration in mice by autophagic degradation of GSK3β.
    Xiao Chen Shi, Bo Xia, Jian Feng Zhang, Rui Xin Zhang, Dan Yang Zhang, Huan Liu, Bao Cai Xie, Yong Liang Wang, Jiang Wei Wu.
      Skeletal muscle regeneration is essential for maintaining muscle function in injury and muscular disease. Myogenesis plays key roles in forming new myofibers during the process. Here, through bioinformatic screen for the potential regulators of myogenesis from 5 independent microarray datasets, we identify an overlapping differentially expressed gene (DEG) optineurin (OPTN). Optn knockdown (KD) delays muscle regeneration in mice and impairs C2C12 myoblast differentiation without affecting their proliferation. Conversely, Optn overexpression (OE) promotes myoblast differentiation. Mechanistically, OPTN increases nuclear levels of β-catenin and enhances the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription activity, suggesting activation of Wnt signaling pathway. The activation is accompanied by decreased protein levels of glycogen synthase kinase 3β (GSK3β), a negative regulator of the pathway. We further show that OPTN physically interacts with and targets GSK3β for autophagic degradation. Pharmacological inhibition of GSK3β rescues the impaired myogenesis induced by Optn KD during muscle regeneration and myoblast differentiation, corroborating that GSK3β is the downstream effector of OPTN-mediated myogenesis. Together, our study delineates the novel role of OPTN as a potential regulator of myogenesis and may open innovative therapeutic perspectives for muscle regeneration.
    DOI:  https://doi.org/10.1371/journal.pbio.3001619
  44. Front Cell Neurosci. 2022 ;16 853634
    Neuronal mTOR Outposts: Implications for Translation, Signaling, and Plasticity.
    Bekir Altas, Andrea J Romanowski, Garrett W Bunce, Alexandros Poulopoulos.
      The kinase mTOR is a signaling hub for pathways that regulate cellular growth. In neurons, the subcellular localization of mTOR takes on increased significance. Here, we review findings on the localization of mTOR in axons and offer a perspective on how these may impact our understanding of nervous system development, function, and disease. We propose a model where mTOR accumulates in local foci we term mTOR outposts, which can be found in processes distant from a neuron's cell body. In this model, pathways that funnel through mTOR are gated by local outposts to spatially select and amplify local signaling. The presence or absence of mTOR outposts in a segment of axon or dendrite may determine whether regional mTOR-dependent signals, such as nutrient and growth factor signaling, register toward neuron-wide responses. In this perspective, we present the emerging evidence for mTOR outposts in neurons, their putative roles as spatial gatekeepers of signaling inputs, and the implications of the mTOR outpost model for neuronal protein synthesis, signal transduction, and synaptic plasticity.
    Keywords:  axon; axon regeneration; ketamine; local translation; mTOR; ribosome biogenesis; synapse tagging
    DOI:  https://doi.org/10.3389/fncel.2022.853634
  45. Theriogenology. 2022 Apr 15. pii: S0093-691X(22)00148-0. [Epub ahead of print]186 155-167
    2-Mercaptoethanol promotes porcine oocyte maturation in vitro by maintaining autophagy homeostasis.
    Yaping Zhang, Qiqi Li, Wangchang Li, Ke Yan, Yaru Liu, Huiyan Xu, Mingsheng Jiang, Yangqing Lu, Xingwei Liang, Jianghua Shang, Xiaogan Yang.
      2-Mercaptoethanol (2-ME) is often used as an antioxidant to optimize culture systems for in vitro oocyte maturation in livestock. However, the relationship between 2-ME and autophagy has not yet been elucidated. In this study, we hypothesized that 2-ME can promote porcine oocyte maturation in vitro by maintaining autophagy homeostasis. To test this hypothesis, we explored the effects of 2-ME on the maturation of porcine oocytes exposed to an autophagy activator (rapamycin) or an autophagy inhibitor (3-methyladenine, i.e., 3-MA) in vitro. Rapamycin-induced autophagy over-activation significantly increased autophagy- and apoptosis-related gene expression, oxidative stress, apoptosis rates, abnormal mitochondrial redistribution, and significantly decreased oocyte first polar body extrusion (PBE) rates, spindle/chromosome integrity and developmental competence. 3-MA-mediated autophagy inhibition exerted similar effects on all these parameters except the expression of genes that promote autophagy and inhibit apoptosis. Importantly, 2-ME supplementation significantly attenuated the detrimental effects of rapamycin and 3-MA. Interestingly, we observed that 44 h of coincubation with rapamycin/3-MA and 2-ME restored autophagy homeostasis in vitro. In conclusion, our study confirmed that 2-ME promotes porcine oocyte maturation and embryo development in vitro by maintaining autophagy homeostasis and lays a foundation for further research on the underlying mechanism.
    Keywords:  2-Mercaptoethanol; Autophagy disorders; In vitro maturation; Oocyte; Porcine; Protective effects
    DOI:  https://doi.org/10.1016/j.theriogenology.2022.04.009
  46. Front Cell Dev Biol. 2022 ;10 852028
    Golgi-Bypass Is a Major Unconventional Route for Translocation to the Plasma Membrane of Non-Apical Membrane Cargoes in Aspergillus nidulans.
    Sofia Dimou, Mariangela Dionysopoulou, Georgia Maria Sagia, George Diallinas.
      Nutrient transporters have been shown to translocate to the plasma membrane (PM) of the filamentous fungus Aspergillus nidulans via an unconventional trafficking route that bypasses the Golgi. This finding strongly suggests the existence of distinct COPII vesicle subpopulations, one following Golgi-dependent conventional secretion and the other directed towards the PM. Here, we address whether Golgi-bypass concerns cargoes other than nutrient transporters and whether Golgi-bypass is related to cargo structure, size, abundance, physiological function, or polar vs. non-polar distribution in the PM. To address these questions, we followed the dynamic subcellular localization of two selected membrane cargoes differing in several of the aforementioned aspects. These are the proton-pump ATPase PmaA and the PalI pH signaling component. Our results show that neosynthesized PmaA and PalI are translocated to the PM via Golgi-bypass, similar to nutrient transporters. In addition, we showed that the COPII-dependent exit of PmaA from the ER requires the alternative COPII coat subunit LstA, rather than Sec24, whereas PalI requires the ER cargo adaptor Erv14. These findings strengthen the evidence of distinct cargo-specific COPII subpopulations and extend the concept of Golgi-independent biogenesis to essential transmembrane proteins, other than nutrient transporters. Overall, our findings point to the idea that Golgi-bypass might not constitute a fungal-specific peculiarity, but rather a novel major and cargo-specific sorting route in eukaryotic cells that has been largely ignored.
    Keywords:  COPII; Pma1; endoplasmic reticulum; fungi; pH sensing; polarity; secretion; traffic
    DOI:  https://doi.org/10.3389/fcell.2022.852028
  47. Food Chem Toxicol. 2022 Apr 26. pii: S0278-6915(22)00269-1. [Epub ahead of print]164 113071
    Endogenous hydrogen sulfide counteracts polystyrene nanoplastics-induced mitochondrial apoptosis and excessive autophagy via regulating Nrf2 and PGC-1α signaling pathway in mouse spermatocyte-derived GC-2spd(ts) cells.
    Siwen Li, Yu Ma, Shuzi Ye, Ying Su, Die Hu, Fang Xiao.
      Nanoplastics (NaPs) has reported to accumulate in the testes and cause degeneration in the seminiferous tubules. Additionally, exogenous hydrogen sulfide (H2S) is proposed to enhance tolerance to oxidative stress. The current work aimed to investigate the mechanisms of NaPs-induced reproductive toxicity in vitro and probable reproductive protection by endogenous H2S. We firstly found that 80 nm fluorescent NaPs could enter into GC-2spd(ts) cells by fluorescent inverted microscope. In addition, we demonstrated that NaPs-induced could induce ROS-dependent mitochondrial apoptosis and autophagy in vitro. Our results showed that the H2S donor NaHS ameliorated NaPs-triggered mitochondrial apoptosis and autophagy in GC-2spd(ts) cells. Moreover, NaPs treatment did not change the interaction between nuclear factor erythroid-derived 2-related factor (Nrf2) and Kelch-like ECH associated protein 1 (Keap1), while inhibiting nuclear accumulation of Nrf2 protein was observed. Meanwhile, NaHS weakened this interaction, subsequently improving antioxidant ability via increasing the protein levels of heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1). Further, invitro experiments showed that NaPs-induced reproductive toxicity associated with reducing PGC-1α. Meanwhile, NaPs-induced higher expression PGC-1α was further enhanced by NaHS co-treatment. Together, this study highlight that exogenous H2S should be an essential therapeutic approach to alleviate NaPs-induced reproductive toxicity via regulating Nrf2/PGC-1α signal.
    Keywords:  Mitochondrial apoptosis; Nanoplastics; Nuclear factor erythroid-derived 2-related factor (Nrf2); Pyruvate kinase M2; Reproductive toxicity
    DOI:  https://doi.org/10.1016/j.fct.2022.113071
  48. J Mater Chem B. 2022 Apr 26.
    Rational engineering of biomimetic flavylium fluorophores for regulating the lysosomal and mitochondrial localization behavior by pH-induced structure switch and application to fluorescence imaging.
    Liping Wang, Mengye He, Yu Sun, Li Liu, Yuan Ye, Lingrong Liu, Xing-Can Shen, Hua Chen.
      Mitochondria and lysosomes, as the important subcellular organelles, play vital roles in cell metabolism and physiopathology. However, there is still no general method to precisely regulate the lysosomal and mitochondrial localization behavior of fluorescent probes except by selecting specific targeting groups. Herein, we proposed a pH-induced structure switch (pHISS) strategy to solve this tricky puzzle. For the proof-of-concept, we have rationally designed and synthesized a series of cationic flavylium derivatives FL-1-9 with tunable pH-induced structure switch through adjusting the electron-donating ability of the substituents. As expected, the co-localization imaging experiments revealed that the lysosomal and mitochondrial localization behavior of FL-1-9 dyes is closely related to their pHISS ability. It is noteworthy that FL cationic dyes with strong electron-donors are not prone to pHISS and can be well enriched in mitochondria, while FL cationic dyes with weak electron-donors are highly susceptible to pHISS and display an unusual lysosome-targeting capability. This also provided a feasible strategy for lysosomal localization without basic groups and presented new application options for some flavylium dyes previously thought to be less stable. Furthermore, FL cationic dyes with medium electron-donor exhibit certain localization abilities both in mitochondria and lysosomes. Finally, through a detailed study of pH-induced structure switch and exploiting the pH inertia brought by the strong electron-donors, a novel NIR ratiometric fluorescent probe with large wavelength-shift was constructed for monitoring mitochondrial H2S in living cells, tumor tissues and living mice, highlighting the value of the pHISS strategy in precisely regulating organelle targeting and constructing corresponding organelle targeting probes.
    DOI:  https://doi.org/10.1039/d2tb00181k
  49. Biochem Biophys Res Commun. 2022 Apr 20. pii: S0006-291X(22)00605-2. [Epub ahead of print]611 23-30
    MCC950 ameliorates the dementia symptom at the early age of line M83 mouse and reduces hippocampal α-synuclein accumulation.
    Yu Ren, Qing Wang, Zexian Yang, Linyin Feng, Yu Zhang.
      Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia after Alzheimer's disease (AD). Neuroinflammation plays an important role in neurodegenerative diseases. It is urgent to unravel the pathogenesis of DLB and find potential therapeutic drugs. Here, we investigated the pharmacological effects of the NLRP3 inflammasome inhibitor MCC950 in A53T α-synuclein transgenic line M83 mice aged 4 months. The behavioral tests including Y-maze, Barnes maze, nest building and Rotarod showed that MCC950 significantly improved the cognitive dysfunction symptom without affecting the motor coordination after consecutive intragastric administration every day for 5 weeks. Furthermore, immunostaining or immunoblotting experiments on the hippocampal tissue were performed, and the results suggested that MCC950 not only inhibited the expression of NLRP3, and suppressed the activation of astrocytes and microglia, but also promoted the mTOR-mediated autophagy pathway to reduce human α-synuclein accumulation. Our findings further demonstrate that line M83 mice may be used as an animal model for DLB research, and can provide preclinical evidences for the development of MCC950 as a promising therapeutic drug.
    Keywords:  A53T α-synuclein; Autophagy; Dementia; Line M83; MCC950
    DOI:  https://doi.org/10.1016/j.bbrc.2022.04.076
  50. Blood. 2022 Apr 26. pii: blood.2021014493. [Epub ahead of print]
    Targeted autophagy disruption reveals the central role of macrophage iron metabolism in systemic iron homeostasis.
    Meriem Taleb, Isabelle Maillet, Marc Le Bert, Catherine Mura.
      Iron homeostasis depends on both intracellular control through iron-responsive proteins and the systemic level of iron through hepcidin-ferroportin axis. Indeed, the hormone hepcidin downregulates the ferroportin iron exporter to control iron recycling from macrophages and iron uptake from enterocytes. Here, we focused on the role of autophagy in macrophage iron metabolism and systemic iron homeostasis. Mice deficient for autophagy in macrophages (LysM-Atg5-/-) mimicked a primary iron overload phenotype, resulting in high ferroportin expression in both macrophages and enterocytes that correlated with marked parenchymal iron overload. Furthermore, LysM-Atg5-/- mice exhibited increased hematopoietic activity with no sign of anemia but correlating with rather high plasma iron level. Compared to wild-type cells, bone marrow-derived macrophages from LysM-Atg5-/- mice had significantly increased ferroportin expression and a decreased iron content, confirming high iron export. In erythrophagocytic macrophages autophagy regulates hemosiderin storage mechanisms as well as the degradation of ferroportin and subsequently its plasma membrane localization and iron export; further, ferroportin colocalization with hepcidin indicates hepcidin autocrine activity. Relatively high hepatic hepcidin expression, and decreased hepcidin level in the spleen of LysM-Atg5-/- mice correlating with low hemosiderin iron storage as well as in erythrophagocytic Atg5-/- macrophages were evidenced. Therefore, our results highligh the critical role of autophagy in macrophages for iron trafficking and systemic iron homeostasis. We propose that in macrophages, autophagy restricts ferroportin level and iron export resulting in hepcidin expression with an autocrine-paracrine effect that takes part in the regulation of the ferroportin expression in duodenal enterocytes.
    DOI:  https://doi.org/10.1182/blood.2021014493
  51. Cell Death Differ. 2022 Apr 24.
    S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders.
    Ki-Ryeong Kim, Eun-Jung Cho, Jae-Won Eom, Sang-Seok Oh, Tomohiro Nakamura, Chang-Ki Oh, Stuart A Lipton, Yang-Hee Kim.
      Protein S-nitrosylation is known to regulate enzymatic function. Here, we report that nitric oxide (NO)-related species can contribute to Alzheimer's disease (AD) by S-nitrosylating the lysosomal protease cathepsin B (forming SNO-CTSB), thereby inhibiting CTSB activity. This posttranslational modification inhibited autophagic flux, increased autolysosomal vesicles, and led to accumulation of protein aggregates. CA-074Me, a CTSB chemical inhibitor, also inhibited autophagic flux and resulted in accumulation of protein aggregates similar to the effect of SNO-CTSB. Inhibition of CTSB activity also induced caspase-dependent neuronal apoptosis in mouse cerebrocortical cultures. To examine which cysteine residue(s) in CTSB are S-nitrosylated, we mutated candidate cysteines and found that three cysteines were susceptible to S-nitrosylation. Finally, we observed an increase in SNO-CTSB in both 5XFAD transgenic mouse and flash-frozen postmortem human AD brains. These results suggest that S-nitrosylation of CTSB inhibits enzymatic activity, blocks autophagic flux, and thus contributes to AD pathogenesis.
    DOI:  https://doi.org/10.1038/s41418-022-01004-0
  52. Food Funct. 2022 Apr 28.
    Apigenin alleviated PA-induced pyroptosis by activating autophagy in hepatocytes.
    Zhuoqun Meng, Beiwei Zhu, Min Gao, Guang Wang, Hongjiang Zhou, Jing Lu, Shuang Guan.
      Apigenin is a kind of natural flavonoid that abundantly exists in fruits and vegetables. Pyroptosis is a new, pro-inflammatory type of programmed necrosis cell death, and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the key molecule to induce pyroptosis. Excessive hepatic pyroptosis results in liver injury. In the study, we found for the first time that apigenin could alleviate palmitic acid (PA)-induced NLRP3 inflammasome activation and pyroptosis in HepG2 cells and primary mouse hepatic cells. Meanwhile, apigenin could promote the autophagy of hepatocytes. When the autophagy inhibitor chloroquine (CQ) was added, the data showed that the recovery effect of apigenin on PA-induced pyroptosis was weakened, indicating that apigenin could alleviate PA-induced pyroptosis by activating autophagy. Further mechanistic studies showed that apigenin regulated the NLRP3 inflammasome through two ways, so as to alleviate PA-induced pyroptosis. On the one hand, apigenin eliminated damaged mitochondria by activating autophagy, thereby clearing reactive oxygen species (ROS) production and inhibiting the activation of the NLRP3 inflammasome, and on the other hand, activation of autophagy could directly degrade the NLRP3 inflammasome. Our study provides a new idea and target for the use of functional factors in food to alleviate liver injury.
    DOI:  https://doi.org/10.1039/d1fo03771d
  53. Bioengineered. 2022 Apr;13(4): 11240-11257
    Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway.
    Lili Song, Shikai Liu, Sufen Zhao.
      Cervical cancer (CC) is the 4th most prevalent malignancy in females. This study explored the mechanism of everolimus (RAD001) combined with programmed death-1 (PD-1) blockade on radiosensitivity by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and autophagy in CC cells. Low-radiosensitive CaSki cells were selected as study objects. After RAD001 treatment, PI3K/AKT/mTOR pathway activation, autophagy, migration and invasion abilities, autophagy-related proteins (LC3-I, LC3-II, and p62), and PD-L1 expression in CC cells were detected. After triple treatment of radiotherapy (RT), RAD001, and PD-1 blockade to the CC mouse models, tumor weight and volume were recorded. Ki67 expression, the number of CD8 + T cells, and the ability to produce IFN-γ and TNF-α in tumor tissues were determined. RAD001 promoted autophagy by repressing PI3K/AKT/mTOR pathway, augmented RT-induced apoptosis, and weakened migration and invasion, thereby increasing CC cell radiosensitivity. RAD001 elevated RT-induced PD-L1 level. RT combined with RAD001 and PD-1 blockade intensified the inhibitory effect of RT on tumor growth, reduced the amount of Ki67-positive cells, enhanced radiosensitivity of CC mice, and increased the quantity and killing ability of CD8 + T cells. Briefly, RAD001 combined with PD-1 blockade increases radiosensitivity of CC by impeding the PI3K/AKT/mTOR pathway and potentiating cell autophagy.
    Keywords:  Cervical cancer; PI3K/AKT/mTOR pathway; T-lymphocytes; autophagy; everolimus; programmed cell death 1 receptor; programmed cell death-ligand 1; radiosensitivity
    DOI:  https://doi.org/10.1080/21655979.2022.2064205
  54. Oncoimmunology. 2022 ;11(1): 2059878
    A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients.
    Julie Le Naour, Zsofia Sztupinszki, Vincent Carbonnier, Odile Casiraghi, Virginie Marty, Lorenzo Galluzzi, Zoltan Szallasi, Guido Kroemer, Erika Vacchelli.
      The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 (ATG16L1) is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn's disease, and epidemiological associations between Crohn's disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association.
    Keywords:  FPR1; Immunogenic cell death; P2RX7; radiotherapy; toll-like receptor
    DOI:  https://doi.org/10.1080/2162402X.2022.2059878
  55. Dalton Trans. 2022 Apr 28.
    Lysosome-targeting luminescent lanthanide complexes: from molecular design to bioimaging.
    D B Ambiliraj, Biju Francis, M L P Reddy.
      Lysosomes are essential acidic cytoplasmic membrane-bound organelles in human cells that play a critical role in many cellular events. A comprehensive understanding of lysosome-specific imaging can ultimately help us to design robust organelle-targeting therapeutic reagents for various underlying human diseases. Luminescent lanthanide molecular materials serve as an important and upcoming class of probes for cellular imaging applications with unique luminescent photophysical features such as sharp emission profiles from the visible to near-infrared spectral regions, long decay lifetimes, attractive quantum yields, large Stokes shifts, and a low propensity to photobleaching. For the last few years, a wide variety of lysosome-targeting luminescent lanthanide probes have been engineered and utilized for the imaging of hypochlorous acid and nitric oxide at the sub-cellular level and these advances are summarized in this review. The design strategies of lanthanide molecular probes, co-localization detection and lysosomal probity assay methods are briefly highlighted. Finally, the future challenges in the development of lysosome-targeting luminescent lanthanide complexes are outlined and emphasized to inspire the design of a new generation of organelle-targeting metal complexes.
    DOI:  https://doi.org/10.1039/d2dt00128d
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