bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023–03–12
fifty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. The autophagy-NAD axis in longevity and disease.
  2. TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
  3. The TORC1 activates Rpd3L complex to deacetylate Ino80 and H2A.Z and repress autophagy.
  4. The role of lysosomes in metabolic and autoimmune diseases.
  5. HCMV-encoded viral protein US12 promotes autophagy by inducing autophagy flux.
  6. STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy.
  7. Impacts of autophagy on the formation of organelle-free zone during the lens development.
  8. Haste makes waste: staged suppression of autophagic-lysosomal pathway in microglia promotes the efficient clearance of myelin debris.
  9. The Role of Mitophagy in Skeletal Muscle Damage and Regeneration.
  10. EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvation.
  11. Modifying dietary protein impacts mTOR signaling and brain deposition of amyloid beta in a knock-in mouse model of Alzheimer's disease.
  12. Mitochondrial mechanisms in Alzheimer's disease: quest for therapeutics.
  13. Autophagy: A Cellular Guardian against Hepatic Lipotoxicity.
  14. A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.
  15. Autophagy in Inflammatory Response against SARS-CoV-2.
  16. Autophagy in Cell Survival and Death.
  17. Transcription factor EB as a key molecular factor in human health and its implication in diseases.
  18. Adipokine gremlin-1 promotes hepatic steatosis via upregulation of ER stress by suppressing autophagy-mediated signaling.
  19. Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome.
  20. Azithromycin, a potent autophagy inhibitor for cancer therapy, perturbs cytoskeletal protein dynamics.
  21. Lysosomal Ion Channels and Lysosome-Organelle Interactions.
  22. Stressing out over mucus secretion.
  23. Research Progress on the Anticancer Molecular Mechanism of Targets Regulating Cell Autophagy.
  24. Lysosomal function and intracellular position determine the malignant phenotype in malignant melanoma.
  25. Myocardial injury: where inflammation and autophagy meet.
  26. S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR2,4, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health.
  27. Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor.
  28. Targeting Autophagy Using Long Non-Coding RNAs (LncRNAs): New Landscapes in the Arena of Cancer Therapeutics.
  29. Rapamycin-Induced Feedback Activation of eIF4E-EIF4A Dependent mRNA Translation in Pancreatic Cancer.
  30. The potential effects of nutrients and light on autophagy-mediated visual function and clearance of retinal aggregates.
  31. Novel approaches to targeted protein degradation technologies in drug discovery.
  32. Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway.
  33. Protein homeostasis in aging and cancer.
  34. The metabolic benefits of exercise-induced hepatic autophagy.
  35. Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective.
  36. Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78.
  37. Identification of critical autophagy-related proteins in diabetic retinopathy: A multi-dimensional computational study.
  38. The Skp1-Cullin1-FBXO1 complex is a pleiotropic regulator required for the formation of gametes and motile forms in Plasmodium berghei.
  39. The Question of Survival or Death: What Is the Role of Autophagy in Acute Myeloid Leukemia (AML)?
  40. A novel role of ATG9A and RB1CC1/FIP200 in mediating cell-death checkpoints to repress TNF cytotoxicity.
  41. Depletion of Paraoxonase 1 (Pon1) Dysregulates mTOR, Autophagy, and Accelerates Amyloid Beta Accumulation in Mice.
  42. Defective Chaperone-mediated Autophagy is a Hallmark of Joint Disease in Patients with Knee Osteoarthritis.
  43. Tau, RNA, and RNA-Binding Proteins: Complex Interactions in Health and Neurodegenerative Diseases.
  44. Regional and age-dependent changes in ubiquitination in cellular and mouse models of Spinocerebellar ataxia type 3.
  45. New discoveries in ER-mitochondria communication.
  46. 3,4-benzopyrene aggravates myocardial ischemia-reperfusion injury-induced pyroptosis through inhibition of autophagy-dependent NLRP3 degradation.
  47. Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.
  48. Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.
  49. Molecular Regulation of Autophagy and Asymmetric Cell Division by Cancer Stem Cell Marker CD133.
  50. RIOK3 promotes mTORC1 activation by facilitating SLC7A2-mediated arginine uptake in pancreatic ductal adenocarcinoma.
  51. Lysosomal trafficking of the glucose transporter GLUT1 requires sequential regulation by TXNIP and ubiquitin.
  52. Cathepsin B maturation plays a critical role in leptin-induced hepatic cancer cell growth through activation of NLRP3 inflammasomes.
  53. Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK.
  54. 1α,25(OH)2D3 Promotes the Autophagy of Porcine Ovarian Granulosa Cells as a Protective Mechanism against ROS through the BNIP3/PINK1 Pathway.
  1. Trends Cell Biol. 2023 Mar 04. pii: S0962-8924(23)00023-5. [Epub ahead of print]
    The autophagy-NAD axis in longevity and disease.
    Niall Wilson, Tetsushi Kataura, Miriam E Korsgen, Congxin Sun, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.
    Keywords:  PARP; Parkinson's disease; ageing; mitophagy; neurodegeneration; nicotinamide; sirtuins
    DOI:  https://doi.org/10.1016/j.tcb.2023.02.004
  2. Mol Cell. 2023 Mar 02. pii: S1097-2765(23)00150-8. [Epub ahead of print]
    TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.
    François Le Guerroué, Eric N Bunker, William M Rosencrans, Jack T Nguyen, Mohammed A Basar, Achim Werner, Tsui-Fen Chou, Chunxin Wang, Richard J Youle.
      Mitophagy is a form of selective autophagy that disposes of superfluous and potentially damage-inducing organelles in a tightly controlled manner. While the machinery involved in mitophagy induction is well known, the regulation of the components is less clear. Here, we demonstrate that TNIP1 knockout in HeLa cells accelerates mitophagy rates and that ectopic TNIP1 negatively regulates the rate of mitophagy. These functions of TNIP1 depend on an evolutionarily conserved LIR motif as well as an AHD3 domain, which are required for binding to the LC3/GABARAP family of proteins and the autophagy receptor TAX1BP1, respectively. We further show that phosphorylation appears to regulate its association with the ULK1 complex member FIP200, allowing TNIP1 to compete with autophagy receptors, which provides a molecular rationale for its inhibitory function during mitophagy. Taken together, our findings describe TNIP1 as a negative regulator of mitophagy that acts at the early steps of autophagosome biogenesis.
    Keywords:  FIP200; FIR; LIR; Selective autophagy; TAX1BP1; TBK1; TNIP1; mitophagy; mitophagy regulation
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.023
  3. Sci Adv. 2023 Mar 10. 9(10): eade8312
    The TORC1 activates Rpd3L complex to deacetylate Ino80 and H2A.Z and repress autophagy.
    Xin Li, Qianyun Mei, Qi Yu, Min Wang, Fei He, Duncheng Xiao, Huan Liu, Feng Ge, Xilan Yu, Shanshan Li.
      Autophagy is a critical process to maintain homeostasis, differentiation, and development. How autophagy is tightly regulated by nutritional changes is poorly understood. Here, we identify chromatin remodeling protein Ino80 and histone variant H2A.Z as the deacetylation targets for histone deacetylase Rpd3L complex and uncover how they regulate autophagy in response to nutrient availability. Mechanistically, Rpd3L deacetylates Ino80 K929, which protects Ino80 from being degraded by autophagy. The stabilized Ino80 promotes H2A.Z eviction from autophagy-related genes, leading to their transcriptional repression. Meanwhile, Rpd3L deacetylates H2A.Z, which further blocks its deposition into chromatin to repress the transcription of autophagy-related genes. Rpd3-mediated deacetylation of Ino80 K929 and H2A.Z is enhanced by the target of rapamycin complex 1 (TORC1). Inactivation of TORC1 by nitrogen starvation or rapamycin inhibits Rpd3L, leading to induction of autophagy. Our work provides a mechanism for chromatin remodelers and histone variants in modulating autophagy in response to nutrient availability.
    DOI:  https://doi.org/10.1126/sciadv.ade8312
  4. Nat Rev Nephrol. 2023 Mar 09.
    The role of lysosomes in metabolic and autoimmune diseases.
    Frédéric Gros, Sylviane Muller.
      Lysosomes are catabolic organelles that contribute to the degradation of intracellular constituents through autophagy and of extracellular components through endocytosis, phagocytosis and macropinocytosis. They also have roles in secretory mechanisms, the generation of extracellular vesicles and certain cell death pathways. These functions make lysosomes central organelles in cell homeostasis, metabolic regulation and responses to environment changes including nutrient stresses, endoplasmic reticulum stress and defects in proteostasis. Lysosomes also have important roles in inflammation, antigen presentation and the maintenance of long-lived immune cells. Their functions are tightly regulated by transcriptional modulation via TFEB and TFE3, as well as by major signalling pathways that lead to activation of mTORC1 and mTORC2, lysosome motility and fusion with other compartments. Lysosome dysfunction and alterations in autophagy processes have been identified in a wide variety of diseases, including autoimmune, metabolic and kidney diseases. Deregulation of autophagy can contribute to inflammation, and lysosomal defects in immune cells and/or kidney cells have been reported in inflammatory and autoimmune pathologies with kidney involvement. Defects in lysosomal activity have also been identified in several pathologies with disturbances in proteostasis, including autoimmune and metabolic diseases such as Parkinson disease, diabetes mellitus and lysosomal storage diseases. Targeting lysosomes is therefore a potential therapeutic strategy to regulate inflammation and metabolism in a variety of pathologies.
    DOI:  https://doi.org/10.1038/s41581-023-00692-2
  5. Biochem Biophys Res Commun. 2023 Mar 04. pii: S0006-291X(23)00274-7. [Epub ahead of print]654 94-101
    HCMV-encoded viral protein US12 promotes autophagy by inducing autophagy flux.
    Hyung Jin Kim, Yoora Lee, Sungwook Lee, Boyoun Park.
      The human cytomegalovirus (HCMV)-encoded US12 gene family is a group of ten predicted seven-transmembrane domain proteins that are structurally similar to G-protein-coupled receptors or transmembrane Bax inhibitor-1 motif-containing proteins; however, the roles of US12 family proteins in virus-host interactions remain to be discovered. Here, we suggest a new function of the US12 protein in regulating cellular autophagy. US12 is predominantly located to the lysosome and interacts with the lysosomal membrane protein 2 (LAMP2). A liquid chromatography-mass spectrometry (MS)/MS-based targeted proteomics analysis shows that US12 is tightly correlated with autophagy. US12 induces autophagy via upregulating ULK1 phosphorylation and subsequent LC3-II conversion, thereby accelerating autophagic flux. Moreover, HeLa cells overexpressing US12 displays intense LC3-specific staining and autolysosome formation even under nutrient-sufficient conditions. Furthermore, the physical interaction of p62/SQSTM1 with US12 is involved in the resistance to the degradation of p62/SQSTM1 by autophagy, despite the induction of both autolysosome formation and autophagic flux. Although the effect of US12 expression in HCMV infection on autophagy remains undetermined, these findings provide new insights into the viral drivers of host autophagy during HCMV evolution and pathogenesis.
    Keywords:  Autophagy; Human cytomegalovirus; Infection; US12 gene family
    DOI:  https://doi.org/10.1016/j.bbrc.2023.03.004
  6. EMBO J. 2023 Mar 06. e112387
    STING directly recruits WIPI2 for autophagosome formation during STING-induced autophagy.
    Wei Wan, Chuying Qian, Qian Wang, Jin Li, Hongtao Zhang, Lei Wang, Maomao Pu, Yewei Huang, Zhengfu He, Tianhua Zhou, Han-Ming Shen, Wei Liu.
      The cGAS-STING pathway plays an important role in host defense by sensing pathogen DNA, inducing type I IFNs, and initiating autophagy. However, the molecular mechanism of autophagosome formation in cGAS-STING pathway-induced autophagy is still unclear. Here, we report that STING directly interacts with WIPI2, which is the key protein for LC3 lipidation in autophagy. Binding to WIPI2 is necessary for STING-induced autophagosome formation but does not affect STING activation and intracellular trafficking. In addition, the specific interaction between STING and the PI3P-binding motif of WIPI2 leads to the competition of WIPI2 binding between STING and PI3P, and mutual inhibition between STING-induced autophagy and canonical PI3P-dependent autophagy. Furthermore, we show that the STING-WIPI2 interaction is required for the clearance of cytoplasmic DNA and the attenuation of cGAS-STING signaling. Thus, the direct interaction between STING and WIPI2 enables STING to bypass the canonical upstream machinery to induce LC3 lipidation and autophagosome formation.
    Keywords:  STING; WIPI2; autophagy; cGAS; cytoplasmic DNA
    DOI:  https://doi.org/10.15252/embj.2022112387
  7. Mol Biol Rep. 2023 Mar 06.
    Impacts of autophagy on the formation of organelle-free zone during the lens development.
    Hongyu Li, Lixiong Gao, Jinlin Du, Tianju Ma, Wen Li, Zi Ye, Zhaohui Li.
      The thorough degeneration of organelles in the core of the lens is certainly a hallmark event during the lens development. Organelles degradation in the terminal differentiation process of lens fiber cells to form an organelle-free zone is critical for lens maturation and transparency. Several mechanisms have been proposed to expand our understanding of lens organelles degradation, including apoptotic pathways, the participation of ribozyme, proteolytic enzyme and phospholipase A and acyltransferase, and the newly discovered roles for autophagy. Autophagy is a lysosome-dependent degradation reaction during which the "useless" cellular components are degraded and recycled. These cellular components, such as incorrectly folded proteins, damaged organelles and other macromolecules, are first engulfed by the autophagosome before being further delivered to lysosomes for degradation. Although autophagy has been recognized involving in organelle degradation of the lens, the detailed functions remain to be discovered. Recent advances have revealed that autophagy not only plays a vital role in the intracellular quality control of the lens but is also involved in the degradation of nonnuclear organelles in the process of lens fiber cell differentiation. Herein, we first review the potential mechanisms of organelle-free zone formation, then discuss the roles of autophagy in intracellular quality control and cataract formation, and finally substantially summarize the potential involvement of autophagy in the development of organelle-free zone formation.
    Keywords:  Autophagy; Lens development; Organelle-free zone
    DOI:  https://doi.org/10.1007/s11033-023-08323-6
  8. Autophagy. 2023 Mar 05. 1-3
    Haste makes waste: staged suppression of autophagic-lysosomal pathway in microglia promotes the efficient clearance of myelin debris.
    Chuan Qin, Yun-Hui Chu, Luo-Qi Zhou, Ming-Hao Dong, Wei Wang, Dai-Shi Tian.
      The autophagic-lysosomal pathway of microglia plays a key role in myelin debris removal in white matter damage. As the lipid-rich myelin debris are engulfed by microglia, the cellular autophagic level increases, accompanied by lysosomal dysfunction. However, several issues such as how to regulate this pathway to ensure the effective degradation of myelin debris, and maintain the balance of lipid metabolism are still to be elucidated. Recently, we have demonstrated that the excessive activation of macroautophagy/autophagy leads to lipid overload in lysosomes and lipid droplets accumulation, which could be the initiator of microglial dysfunction and secondary inflammatory white matter damage. Interestingly, staged suppression of autophagic activation in the acute phase of demyelination could benefit microglia allowing them to regain the lipid metabolism balance, and reduce the excessive accumulation of lipids, thus promoting the removal of myelin debris. The neuroprotective effects of microglial autophagy regulation may be related to intracellular linoleic acid (LA) production and PPARG pathway activation.
    Keywords:  Autophagy; linoleic acid; microglia; myelin debris; staged suppression
    DOI:  https://doi.org/10.1080/15548627.2023.2186097
  9. Cells. 2023 Feb 24. pii: 716. [Epub ahead of print]12(5):
    The Role of Mitophagy in Skeletal Muscle Damage and Regeneration.
    Eirini Chatzinikita, Maria Maridaki, Konstantinos Palikaras, Michael Koutsilieris, Anastassios Philippou.
      Mitochondria are cellular organelles that play an essential role in generating the chemical energy needed for the biochemical reactions in cells. Mitochondrial biogenesis, i.e., de novo mitochondria formation, results in enhanced cellular respiration, metabolic processes, and ATP generation, while autophagic clearance of mitochondria (mitophagy) is required to remove damaged or useless mitochondria. The balance between the opposing processes of mitochondrial biogenesis and mitophagy is highly regulated and crucial for the maintenance of the number and function of mitochondria as well as for the cellular homeostasis and adaptations to metabolic demands and extracellular stimuli. In skeletal muscle, mitochondria are essential for maintaining energy homeostasis, and the mitochondrial network exhibits complex behaviors and undergoes dynamic remodeling in response to various conditions and pathologies characterized by changes in muscle cell structure and metabolism, such as exercise, muscle damage, and myopathies. In particular, the involvement of mitochondrial remodeling in mediating skeletal muscle regeneration following damage has received increased attention, as modifications in mitophagy-related signals arise from exercise, while variations in mitochondrial restructuring pathways can lead to partial regeneration and impaired muscle function. Muscle regeneration (through myogenesis) following exercise-induced damage is characterized by a highly regulated, rapid turnover of poor-functioning mitochondria, permitting the synthesis of better-functioning mitochondria to occur. Nevertheless, essential aspects of mitochondrial remodeling during muscle regeneration remain poorly understood and warrant further characterization. In this review, we focus on the critical role of mitophagy for proper muscle cell regeneration following damage, highlighting the molecular mechanisms of the mitophagy-associated mitochondrial dynamics and network reformation.
    Keywords:  exercise; mitochondrial biogenesis; mitochondrial network; mitophagy; muscle damage; myogenesis; regeneration
    DOI:  https://doi.org/10.3390/cells12050716
  10. PLoS Biol. 2023 Mar;21(3): e3002034
    EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvation.
    Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Susanna Ambrosio, Rossella De Cegli, Margherita Mutarelli, Lorenzo Vaccaro, Micheal J Ziller, Davide Cacchiarelli, Diego L Medina, Andrea Ballabio.
      The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the proliferation of 2D and 3D cultures of cells displaying constitutive activation of TFEB, including those from a patient with Birt-Hogg-Dubé (BHD) syndrome, a TFEB-driven inherited cancer condition. Overall, we uncover an additional layer of TFEB regulation consisting in modulating its transcription via EGR1 and propose that interfering with the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
    DOI:  https://doi.org/10.1371/journal.pbio.3002034
  11. J Nutr. 2023 Mar 02. pii: S0022-3166(23)35277-5. [Epub ahead of print]
    Modifying dietary protein impacts mTOR signaling and brain deposition of amyloid beta in a knock-in mouse model of Alzheimer's disease.
    Julien Bensalem, Leanne K Hein, Sofia Hassiotis, Paul J Trim, Christopher G Proud, Leonie K Heilbronn, Timothy J Sargeant.
       BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition defined by the build-up of amyloid plaques in the brain and intraneuronal tangles of the protein tau. Autophagy is a cellular cleaning process involved in the degradation of proteins, including proteins directly responsible for amyloid plaques, but its activity is compromised in AD. The mechanistic target of rapamycin complex 1 (mTORC1) inhibits autophagy when activated by amino acids.
    OBJECTIVES: We therefore hypothesized that reducing amino acid intake by decreasing dietary protein could promote autophagy which in turn could prevent amyloid plaque deposition in mice.
    METHODS: Homozygote (2-month old) and heterozygote (4-month old) amyloid precursor protein (APP) NL-G-F mice, a model of brain amyloid deposition, were used in this study to test this hypothesis. Male and female mice were fed one of three isocaloric low-protein, control, or high-protein diets for four months and then humanely killed for analysis. Locomotor performance was measured using the inverted screen test and body composition was measured using EchoMRI. Samples were analyzed using western blotting, enzyme-linked immunosorbent assay (ELISA), mass spectrometry, and immunohistochemical staining.
    RESULTS: mTORC1 activity in the cerebral cortex was inversely co-varied with protein consumption in both homozygote and heterozygote mice. Low-protein diet improved metabolic parameters and restored locomotor performance only in male homozygous mice. Dietary protein adjustment did not impact amyloid deposition in homozygous mice. However, in the heterozygous APP NL-G-F mice, amyloid plaque was lower in male mice consuming the low-protein compared with control diet.
    CONCLUSIONS: Thus, reducing protein intake reduces mTORC1 activity and may prevent amyloid accumulation, at least in male mice. This study shows that dietary protein is a tool that can be used to change mTORC1 activity and amyloid deposition in the mouse brain and also demonstrates that the murine brain's response to dietary protein is sex specific.
    Keywords:  Alzheimer’s disease; autophagy; diet; mTOR; macronutrient
    DOI:  https://doi.org/10.1016/j.tjnut.2023.02.035
  12. Drug Discov Today. 2023 Mar 03. pii: S1359-6446(23)00063-6. [Epub ahead of print] 103547
    Mitochondrial mechanisms in Alzheimer's disease: quest for therapeutics.
    Komal Kalani, Poonam Chaturvedi, Pankaj Chaturvedi, Vinod Kumar Verma, Nand Lal, Sudhir K Awasthi, Anuradha Kalani.
      Mitochondrial function is essential for maintaining neuronal integrity, because neurons have a high energy demand. Neurodegenerative diseases, such as Alzheimer's disease (AD), are exacerbated by mitochondrial dysfunction. Mitochondrial autophagy (mitophagy) attenuates neurodegenerative diseases by eradicating dysfunctional mitochondria. In neurodegenerative disorders, there is disruption of the mitophagy process. High levels of iron also interfere with the mitophagy process and the mtDNA released after mitophagy is proinflammatory and triggers the cGAS-STING pathway that aids AD pathology. In this review, we critically discuss the factors that affect mitochondrial impairment and different mitophagy processes in AD. Furthermore, we discuss the molecules used in mouse studies as well as clinical trials that could result in potential therapeutics in the future. Teaser: This review reports the novel therapeutic molecules that are underway in clinical trials for neurodegenerative diseases like Alzheimer's disease, demonstrating how mitochondria become dysfunctional and how they can be rescued.
    Keywords:  Alzheimer’s disease; bioenergetics; exosomes; mitochondria; mitophagy; neurodegenerative disorders
    DOI:  https://doi.org/10.1016/j.drudis.2023.103547
  13. Genes (Basel). 2023 Feb 23. 14(3): 553
    Autophagy: A Cellular Guardian against Hepatic Lipotoxicity.
    Rohit Anthony Sinha.
      Lipotoxicity is a phenomenon of lipid-induced cellular injury in nonadipose tissue. Excess of free saturated fatty acids (SFAs) contributes to hepatic injury in nonalcoholic fatty liver disease (NAFLD), which has been growing at an unprecedented rate in recent years. SFAs and their derivatives such as ceramides and membrane phospholipids have been shown to induce intrahepatic oxidative damage and ER stress. Autophagy represents a cellular housekeeping mechanism to counter the perturbation in organelle function and activation of stress signals within the cell. Several aspects of autophagy, including lipid droplet assembly, lipophagy, mitophagy, redox signaling and ER-phagy, play a critical role in mounting a strong defense against lipotoxic lipid species within the hepatic cells. This review provides a succinct overview of our current understanding of autophagy-lipotoxicity interaction and its pharmacological and nonpharmacological modulation in treating NAFLD.
    Keywords:  ER stress; NAFLD; NASH; autophagy; lipotoxicity; oxidative stress
    DOI:  https://doi.org/10.3390/genes14030553
  14. EMBO J. 2023 Mar 10. e113033
    A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.
    Yu Cao, Jing Zheng, Huayun Wan, Yuqiu Sun, Song Fu, Shanshan Liu, Baiyu He, Gaihong Cai, Yang Cao, Huanwei Huang, Qi Li, Yan Ma, She Chen, Fengchao Wang, Hui Jiang.
      Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria-targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation. Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.
    Keywords:  BNIP3/NIX; FBXL4; mitochondrial disease; mitophagy; ubiquitin-proteasome pathway
    DOI:  https://doi.org/10.15252/embj.2022113033
  15. Int J Mol Sci. 2023 Mar 03. pii: 4928. [Epub ahead of print]24(5):
    Autophagy in Inflammatory Response against SARS-CoV-2.
    Roxana Resnik, Fabiana Lopez Mingorance, Francisco Rivera, Florencia Mitchell, Claudio D Gonzalez, Maria I Vaccaro.
      The coronavirus disease pandemic, which profoundly reshaped the world in 2019 (COVID-19), and is currently ongoing, has affected over 200 countries, caused over 500 million cumulative cases, and claimed the lives of over 6.4 million people worldwide as of August 2022. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Depicting this virus' life cycle and pathogenic mechanisms, as well as the cellular host factors and pathways involved during infection, has great relevance for the development of therapeutic strategies. Autophagy is a catabolic process that sequesters damaged cell organelles, proteins, and external invading microbes, and delivers them to the lysosomes for degradation. Autophagy would be involved in the entry, endo, and release, as well as the transcription and translation, of the viral particles in the host cell. Secretory autophagy would also be involved in developing the thrombotic immune-inflammatory syndrome seen in a significant number of COVID-19 patients that can lead to severe illness and even death. This review aims to review the main aspects that characterize the complex and not yet fully elucidated relationship between SARS-CoV-2 infection and autophagy. It briefly describes the key concepts regarding autophagy and mentions its pro- and antiviral roles, while also noting the reciprocal effect of viral infection in autophagic pathways and their clinical aspects.
    Keywords:  ATG proteins; COVID-19; MOF; NETosis; SIRS; macroautophagy; mitophagy; pyroptosis
    DOI:  https://doi.org/10.3390/ijms24054928
  16. Int J Mol Sci. 2023 Mar 01. pii: 4744. [Epub ahead of print]24(5):
    Autophagy in Cell Survival and Death.
    Jinsung Yang, Wanil Kim, Deok Ryong Kim.
      Autophagy is a degradative process to remove damaged or unnecessary cellular components, and it has been implicated in many biological processes during cell survival and death [...].
    DOI:  https://doi.org/10.3390/ijms24054744
  17. SAGE Open Med. 2023 ;11 20503121231157209
    Transcription factor EB as a key molecular factor in human health and its implication in diseases.
    Alemu Gebrie.
      Transcription factor EB, as a component of the microphthalmia family of transcription factors, has been demonstrated to be a key controller of autophagy-lysosomal biogenesis. Transcription factor EB is activated by stressors such as nutrition and deprivation of growth factors, hypoxia, lysosomal stress, and mitochondrial injury. To achieve the ultimate functional state, it is controlled in a variety of modes, such as in its rate of transcription, post-transcriptional control, and post-translational alterations. Due to its versatile role in numerous signaling pathways, including the Wnt, calcium, AKT, and mammalian target of rapamycin complex 1 signaling pathways, transcription factor EB-originally identified to be an oncogene-is now well acknowledged as a regulator of a wide range of physiological systems, including autophagy-lysosomal biogenesis, response to stress, metabolism, and energy homeostasis. The well-known and recently identified roles of transcription factor EB suggest that this protein might play a central role in signaling networks in a number of non-communicable illnesses, such as cancer, cardiovascular disorders, drug resistance mechanisms, immunological disease, and tissue growth. The important developments in transcription factor EB research since its first description are described in this review. This review helps to advance transcription factor EB from fundamental research into therapeutic and regenerative applications by shedding light on how important a role it plays in human health and disease at the molecular level.
    Keywords:  Transcription factor EB; autophagy–lysosomal system; signaling pathway
    DOI:  https://doi.org/10.1177/20503121231157209
  18. J Cell Physiol. 2023 Mar 08.
    Adipokine gremlin-1 promotes hepatic steatosis via upregulation of ER stress by suppressing autophagy-mediated signaling.
    Sung Woo Choi, Heeseung Oh, Seung Yeon Park, Wonjun Cho, A M Abd El-Aty, Ahmet Hacimuftuoglu, Ji Hoon Jeong, Tae Woo Jung.
      Gremlin-1 (GR1) is a novel adipokine that is highly expressed in human adipocytes and has been shown to inhibit the BMP2/4-TGFb signaling pathway. It has an effect on insulin sensitivity. Elevated levels of Gremlin have been shown to lead to insulin resistance in skeletal muscle, adipocytes, and hepatocytes. In this study, we investigated the effect of GR1 on hepatic lipid metabolism under hyperlipidemic conditions and explored the molecular mechanisms associated with GR1 by in vitro and in vivo studies. We found that palmitate increased GR1 expression in visceral adipocytes. Recombinant GR1 increased lipid accumulation, lipogenesis, and ER stress markers in cultured primary hepatocytes. Treatment with GR1 increased EGFR expression and mTOR phosphorylation and reduced autophagy markers. EGFR or rapamycin siRNA reduced the effects of GR1 on lipogenic lipid deposition and ER stress in cultured hepatocytes. Administration of GR1 via the tail vein induced lipogenic proteins and ER stress while suppressing autophagy in the livers of experimental mice. Suppression of GR1 by in vivo transfection reduced the effects of a high-fat diet on hepatic lipid metabolism, ER stress, and autophagy in mice. These results suggest that the adipokine GR1 promotes hepatic ER stress due to the impairment of autophagy, ultimately causing hepatic steatosis in the obese state. The current study demonstrated that targeting GR1 may be a potential therapeutic approach for treating metabolic diseases, including metabolic-associated fatty liver disease (MAFLD).
    Keywords:  ER stress; Gremlin-1; MAFLD; autophagy; mTOR
    DOI:  https://doi.org/10.1002/jcp.30982
  19. Front Cell Dev Biol. 2023 ;11 1119773
    Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome.
    Peipei Li, Shen Li, Le Wang, Hongmin Li, Yang Wang, Hongbing Liu, Xin Wang, Xiaodan Zhu, Zhangsuo Liu, Fanglei Ye, Yuan Zhang.
      Sensorineural deafness becomes an inevitable worldwide healthy problem, yet the current curative therapy is limited. Emerging evidences demonstrate mitochondrial dysfunction plays a vital role of in the pathogenesis of deafness. Reactive oxygen species (ROS)-induced mitochondrial dysfunction combined with NLRP3 inflammasome activation is involved in cochlear damage. Autophagy not only clears up undesired proteins and damaged mitochondria (mitophagy), but also eliminate excessive ROS. Appropriate enhancement of autophagy can reduce oxidative stress, inhibit cell apoptosis, and protect auditory cells. In addition, we further discuss the interplays linking ROS generation, NLRP3 inflammasome activation, and autophagy underlying the pathogenesis of deafness, including ototoxic drugs-, noise- and aging-related hearing loss.
    Keywords:  NLRP3 inflammasome; autophagy; hearing loss; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2023.1119773
  20. Br J Cancer. 2023 Mar 04.
    Azithromycin, a potent autophagy inhibitor for cancer therapy, perturbs cytoskeletal protein dynamics.
    Naoharu Takano, Masaki Hiramoto, Yumiko Yamada, Hiroko Kokuba, Mayumi Tokuhisa, Hirotsugu Hino, Keisuke Miyazawa.
       BACKGROUND: Autophagy plays an important role in tumour cell growth and survival and also promotes resistance to chemotherapy. Hence, autophagy has been targeted for cancer therapy. We previously reported that macrolide antibiotics including azithromycin (AZM) inhibit autophagy in various types of cancer cells in vitro. However, the underlying molecular mechanism for autophagy inhibition remains unclear. Here, we aimed to identify the molecular target of AZM for inhibiting autophagy.
    METHODS: We identified the AZM-binding proteins using AZM-conjugated magnetic nanobeads for high-throughput affinity purification. Autophagy inhibitory mechanism of AZM was analysed by confocal microscopic and transmission electron microscopic observation. The anti-tumour effect with autophagy inhibition by oral AZM administration was assessed in the xenografted mice model.
    RESULTS: We elucidated that keratin-18 (KRT18) and α/β-tubulin specifically bind to AZM. Treatment of the cells with AZM disrupts intracellular KRT18 dynamics, and KRT18 knockdown resulted in autophagy inhibition. Additionally, AZM treatment suppresses intracellular lysosomal trafficking along the microtubules for blocking autophagic flux. Oral AZM administration suppressed tumour growth while inhibiting autophagy in tumour tissue.
    CONCLUSIONS: As drug-repurposing, our results indicate that AZM is a potent autophagy inhibitor for cancer treatment, which acts by directly interacting with cytoskeletal proteins and perturbing their dynamics.
    DOI:  https://doi.org/10.1038/s41416-023-02210-4
  21. Handb Exp Pharmacol. 2023 Mar 08.
    Lysosomal Ion Channels and Lysosome-Organelle Interactions.
    Weijie Cai, Ping Li, Mingxue Gu, Haoxing Xu.
      Intracellular organelles exchange their luminal contents with each other via both vesicular and non-vesicular mechanisms. By forming membrane contact sites (MCSs) with ER and mitochondria, lysosomes mediate bidirectional transport of metabolites and ions between lysosomes and organelles that regulate lysosomal physiology, movement, membrane remodeling, and membrane repair. In this chapter, we will first summarize the current knowledge of lysosomal ion channels and then discuss the molecular and physiological mechanisms that regulate lysosome-organelle MCS formation and dynamics. We will also discuss the roles of lysosome-ER and lysosome-mitochondria MCSs in signal transduction, lipid transport, Ca 2+ transfer, membrane trafficking, and membrane repair, as well as their roles in lysosome-related pathologies.
    Keywords:  ER; Lysosomes; Membrane contact sites; Mitochondria; TRPML1
    DOI:  https://doi.org/10.1007/164_2023_640
  22. Cell Host Microbe. 2023 Mar 08. pii: S1931-3128(23)00075-6. [Epub ahead of print]31(3): 327-328
    Stressing out over mucus secretion.
    Michael J Grey.
      In this issue of Cell Host & Microbe, Naama et al. show that autophagy controls mucus secretion in the colons of mice. They demonstrate that autophagy reduces ER stress in mucus-producing goblet cells to enhance mucus production, which shapes the gut microbial community and protects against colitis.
    DOI:  https://doi.org/10.1016/j.chom.2023.02.005
  23. Pharmacology. 2023 Mar 08. 1-14
    Research Progress on the Anticancer Molecular Mechanism of Targets Regulating Cell Autophagy.
    Ting Zhang, Jia Yu, Sha Cheng, Ya Zhang, Chang-Hua Zhou, Juan Qin, Heng Luo.
       BACKGROUND: Autophagy is a lysosome-mediated catabolic process that maintains cell homeostasis and survival. It occurs not only in normal cells such as cardiac muscle cells, neurons, and pancreatic acinar cells but also in various benign and malignant tumors. The abnormal level of intracellular autophagy is closely related to multiple pathophysiological processes, including aging, neurodegeneration, infectious diseases, immune disorders, and cancer. Autophagy mainly plays a dual role in life and death by regulating cell survival, proliferation, and death, thus being involved in the occurrence, development, and treatment of cancer. It is also involved in chemotherapy resistance by a dual role, since it not only promotes the occurrence of drug resistance but also reverses it. Previous findings suggest that the regulation of autophagy can be used as an effective strategy in tumor therapy.
    SUMMARY: Recent studies found that small molecules from natural products and their derivatives exert anticancer activity by regulating the level of autophagy in tumor cells.
    KEY MESSAGES: Therefore, this review article describes the mechanism of autophagy, the role of autophagy in normal cells and tumor cells, and the research progress on the anticancer molecular mechanism of targets regulating cell autophagy. The aim is to provide a theoretical basis for developing autophagy inhibitors or activators to improve anticancer efficacy.
    Keywords:  Anticancer therapy; Autophagy; Cancer
    DOI:  https://doi.org/10.1159/000529279
  24. J Invest Dermatol. 2023 Mar 03. pii: S0022-202X(23)00171-9. [Epub ahead of print]
    Lysosomal function and intracellular position determine the malignant phenotype in malignant melanoma.
    Ida Eriksson, Linda Vainikka, Petra Wäster, Karin Öllinger.
      Lysosomes are central in cell homeostasis and participate in macromolecular degradation, plasma membrane repair, exosome release, cell adhesion/migration and apoptosis. In cancer, alterations in lysosomal function and spatial distribution may facilitate disease progression. In this study we show enhanced lysosomal activity in malignant melanoma cells compared to normal human melanocytes. Most lysosomes show perinuclear location in melanocytes, while they are more dispersed in melanoma, with retained proteolytic activity and low pH also in the peripheral population. Rab7a expression is lower in melanoma cells than in melanocytes and, by increasing Rab7a, lysosomes are relocated to the perinuclear region in melanoma. Exposure to the lysosome destabilizing drug LLOMe (L-leucyl-L-leucine methyl ester) causes higher damage in the perinuclear subset of lysosomes in melanomas, while difference in subpopulation susceptibility cannot be found in melanocytes. Interestingly, melanoma cells recruit the ESCRT-III core protein CHMP4B, involved in lysosomal membrane repair, rather than initiate lysophagy. However, when the perinuclear lysosomal position is promoted by Rab7a overexpression or kinesore treatment, lysophagy is increased. In addition, Rab7a-overexpression is accompanied by reduced migration capacity. Taken together, the study emphasizes that alterations in lysosomal properties facilitate the malignant phenotype and declares the targeting of lysosomal function as a future therapeutic approach.
    Keywords:  LMP; lysosomal positioning; lysosome; malignant melanoma; melanocytes
    DOI:  https://doi.org/10.1016/j.jid.2023.01.036
  25. Burns Trauma. 2023 ;11 tkac062
    Myocardial injury: where inflammation and autophagy meet.
    Chunping Liu, Yanjiao Liu, Huiqi Chen, Xiaofei Yang, Chuanjian Lu, Lei Wang, Jiahong Lu.
      Autophagy is a highly conserved bulk degradation mechanism that degrades damaged organelles, aged proteins and intracellular contents to maintain the homeostasis of the intracellular microenvironment. Activation of autophagy can be observed during myocardial injury, during which inflammatory responses are strongly triggered. Autophagy can inhibit the inflammatory response and regulate the inflammatory microenvironment by removing invading pathogens and damaged mitochondria. In addition, autophagy may enhance the clearance of apoptotic and necrotic cells to promote the repair of damaged tissue. In this paper, we briefly review the role of autophagy in different cell types in the inflammatory microenvironment of myocardial injury and discuss the molecular mechanism of autophagy in regulating the inflammatory response in a series of myocardial injury conditions, including myocardial ischemia, ischemia/reperfusion injury and sepsis cardiomyopathy.
    Keywords:  Autophagy; Inflammation; Myocardial injury
    DOI:  https://doi.org/10.1093/burnst/tkac062
  26. Int J Mol Sci. 2023 Feb 26. pii: 4581. [Epub ahead of print]24(5):
    S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR2,4, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health.
    Shah Alam, Sumaiya Yasmeen Afsar, Gerhild Van Echten-Deckert.
      Astrocytes are critical players in brain health and disease. Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival, and migration. It was shown to be crucial for brain development. Its absence is embryonically lethal, affecting, inter alia, the anterior neural tube closure. However, an excess of S1P due to mutations in S1P-lyase (SGPL1), the enzyme responsible for its constitutive removal, is also harmful. Of note, the gene SGPL1 maps to a region prone to mutations in several human cancers and also in S1P-lyase insufficiency syndrome (SPLIS) characterized by several symptoms, including peripheral and central neurological defects. Here, we investigated the impact of S1P on astrocytes in a mouse model with the neural-targeted ablation of SGPL1. We found that SGPL1 deficiency, and hence the accumulation of its substrate, S1P, causes the elevated expression of glycolytic enzymes and preferentially directs pyruvate into the tricarboxylic acid (TCA) cycle through its receptors (S1PR2,4). In addition, the activity of TCA regulatory enzymes was increased, and consequently, so was the cellular ATP content. The high energy load activates the mammalian target of rapamycin (mTOR), thus keeping astrocytic autophagy in check. Possible consequences for the viability of neurons are discussed.
    Keywords:  S1P-lyase (SGPL1); SPLIS; autophagy; glucose metabolism; sphingosine 1-phosphate (S1P)
    DOI:  https://doi.org/10.3390/ijms24054581
  27. Proc Natl Acad Sci U S A. 2023 Mar 14. 120(11): e2213886120
    Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor.
    Janathan Altuzar, Judith Notbohm, Frank Stein, Per Haberkant, Pia Hempelmann, Saskia Heybrock, Jutta Worsch, Paul Saftig, Doris Höglinger.
      Lysosomes are catabolic organelles involved in macromolecular digestion, and their dysfunction is associated with pathologies ranging from lysosomal storage disorders to common neurodegenerative diseases, many of which have lipid accumulation phenotypes. The mechanism of lipid efflux from lysosomes is well understood for cholesterol, while the export of other lipids, particularly sphingosine, is less well studied. To overcome this knowledge gap, we have developed functionalized sphingosine and cholesterol probes that allow us to follow their metabolism, protein interactions, and their subcellular localization. These probes feature a modified cage group for lysosomal targeting and controlled release of the active lipids with high temporal precision. An additional photocrosslinkable group allowed for the discovery of lysosomal interactors for both sphingosine and cholesterol. In this way, we found that two lysosomal cholesterol transporters, NPC1 and to a lesser extent LIMP-2/SCARB2, bind to sphingosine and showed that their absence leads to lysosomal sphingosine accumulation which hints at a sphingosine transport role of both proteins. Furthermore, artificial elevation of lysosomal sphingosine levels impaired cholesterol efflux, consistent with sphingosine and cholesterol sharing a common export mechanism.
    Keywords:  lysosomal storage diseases; organelle-targeted probes; photocrosslinking; protein–lipid interaction; sphingolipids
    DOI:  https://doi.org/10.1073/pnas.2213886120
  28. Cells. 2023 Mar 06. pii: 810. [Epub ahead of print]12(5):
    Targeting Autophagy Using Long Non-Coding RNAs (LncRNAs): New Landscapes in the Arena of Cancer Therapeutics.
    Aviral Kumar, Sosmitha Girisa, Mohammed S Alqahtani, Mohamed Abbas, Mangala Hegde, Gautam Sethi, Ajaikumar B Kunnumakkara.
      Cancer has become a global health hazard accounting for 10 million deaths in the year 2020. Although different treatment approaches have increased patient overall survival, treatment for advanced stages still suffers from poor clinical outcomes. The ever-increasing prevalence of cancer has led to a reanalysis of cellular and molecular events in the hope to identify and develop a cure for this multigenic disease. Autophagy, an evolutionary conserved catabolic process, eliminates protein aggregates and damaged organelles to maintain cellular homeostasis. Accumulating evidence has implicated the deregulation of autophagic pathways to be associated with various hallmarks of cancer. Autophagy exhibits both tumor-promoting and suppressive effects based on the tumor stage and grades. Majorly, it maintains the cancer microenvironment homeostasis by promoting viability and nutrient recycling under hypoxic and nutrient-deprived conditions. Recent investigations have discovered long non-coding RNAs (lncRNAs) as master regulators of autophagic gene expression. lncRNAs, by sequestering autophagy-related microRNAs, have been known to modulate various hallmarks of cancer, such as survival, proliferation, EMT, migration, invasion, angiogenesis, and metastasis. This review delineates the mechanistic role of various lncRNAs involved in modulating autophagy and their related proteins in different cancers.
    Keywords:  autophagy; cancer; lncRNAs; therapeutics
    DOI:  https://doi.org/10.3390/cells12050810
  29. Cancers (Basel). 2023 Feb 24. pii: 1444. [Epub ahead of print]15(5):
    Rapamycin-Induced Feedback Activation of eIF4E-EIF4A Dependent mRNA Translation in Pancreatic Cancer.
    Trang Uyen Nguyen, Harrison Hector, Eric Nels Pederson, Jianan Lin, Zhengqing Ouyang, Hans-Guido Wendel, Kamini Singh.
      Pancreatic cancer cells adapt molecular mechanisms to activate the protein synthesis to support tumor growth. This study reports the mTOR inhibitor rapamycin's specific and genome-wide effect on mRNA translation. Using ribosome footprinting in pancreatic cancer cells that lack the expression of 4EBP1, we establish the effect of mTOR-S6-dependent mRNAs translation. Rapamycin inhibits the translation of a subset of mRNAs including p70-S6K and proteins involved in the cell cycle and cancer cell growth. In addition, we identify translation programs that are activated following mTOR inhibition. Interestingly, rapamycin treatment results in the translational activation of kinases that are involved in mTOR signaling such as p90-RSK1. We further show that phospho-AKT1 and phospho-eIF4E are upregulated following mTOR inhibition suggesting a feedback activation of translation by rapamycin. Next, targeting eIF4E and eIF4A-dependent translation by using specific eIF4A inhibitors in combination with rapamycin shows significant growth inhibition in pancreatic cancer cells. In short, we establish the specific effect of mTOR-S6 on translation in cells lacking 4EBP1 and show that mTOR inhibition leads to feedback activation of translation via AKT-RSK1-eIF4E signals. Therefore, targeting translation downstream of mTOR presents a more efficient therapeutic strategy in pancreatic cancer.
    Keywords:  CR-1-31B; eIF4A; eIF4E; mTOR; p70-RSK1; ribosome footprinting
    DOI:  https://doi.org/10.3390/cancers15051444
  30. Arch Ital Biol. 2022 Dec 01. 160(3-4): 115-135
    The potential effects of nutrients and light on autophagy-mediated visual function and clearance of retinal aggregates.
    R Pinelli, F Biagioni, E Scaffidi, V Vakunseth Bumah, C L Busceti, S Puglisi-Allegra, G Lazzeri, F Fornai.
      Increasing findings indicate that a dysfunction in the autophagy machinery is common during retinal degeneration. The present article provides evidence showing that an autophagy defect in the outer retinal layers is commonly described at the onset of retinal degeneration. These findings involve a number of structures placed at the border between the inner choroid and the outer retina encompassing the choriocapillaris, the Bruch's membrane, photoreceptors and Mueller cells. At the center of these anatomical substrates are placed cells forming the retinal pigment epithelium (RPE), where autophagy seems to play most of its effects. In fact, a failure of the autophagy flux is mostly severe at the level of RPE. Among various retinal degenerative disorders, age-related macular degeneration (AMD) is mostly affected by a damage to RPE, which can be reproduced by inhibiting the autophagy machinery and it can be counteracted by the activation of the autophagy pathway. In the present manuscript evidence is provided that such a severe impairment of retinal autophagy may be counteracted by administration of a number of phytochemicals, which possess a strong stimulatory activity on autophagy. Likewise, natural light stimulation administered in the form of pulsatile specific wavelengths is capable of inducing autophagy within the retina. This dual approach to stimulate autophagy is further strengthened by the interaction of light with phytochemicals which is shown to activate the chemical properties of these natural molecules in sustaining retinal integrity. The beneficial effects of photo-biomodulation combined with phytochemicals is based on the removal of toxic lipid, sugar and protein species along with the stimulation of mitochondrial turn-over. Additional effects of autophagy stimulation under the combined effects of nutraceuticals and light pulses are discussed concerning stimulation of retinal stem cells which partly correspond to a subpopulation of RPE cells.
    DOI:  https://doi.org/10.12871/000398292022345
  31. Expert Opin Drug Discov. 2023 Mar 09. 1-17
    Novel approaches to targeted protein degradation technologies in drug discovery.
    Yu Xue, Andrew A Bolinger, Jia Zhou.
       INTRODUCTION: Target protein degradation (TPD) provides a novel therapeutic modality, other than inhibition, through the direct depletion of target proteins. Two primary human protein homeostasis mechanisms are exploited: the ubiquitin-proteasome system (UPS) and the lysosomal system. TPD technologies based on these two systems are progressing at an impressive pace.
    AREAS COVERED: This review focuses on the TPD strategies based on UPS and lysosomal system, mainly classified into three types: Molecular Glue (MG), PROteolysis Targeting Chimera (PROTAC), and lysosome-mediated TPD. Starting with a brief background introduction of each strategy, exciting examples and perspectives on these novel approaches are provided.
    EXPERT OPINION: MGs and PROTACs are two major UPS-based TPD strategies that have been extensively investigated in the past decade. Despite some clinical trials, several critical issues remain, among which is emphasized by the limitation of targets. Recently developed lysosomal system-based approaches provide alternative solutions for TPD beyond UPS' capability. The newly emerging novel approaches may partially address issues that have long plagued researchers, such as low potency, poor cell permeability, on-/off-target toxicity, and delivery efficiency. Comprehensive considerations for the rational design of protein degraders and continuous efforts to seek effective solutions are imperative to advance these strategies into clinical medications.
    Keywords:  AUTOphagy-TArgeting Chimera (AUTOTAC); AUtophagy-TArgeting Chimera (AUTAC); AuTophagosome-TEthering Compound (ATTEC); LYsosome-TArgeting Chimera (LYTAC); Molecular Glue (MG); PROteolysis Targeting Chimera (PROTAC); Target Protein Degradation (TPD); Ubiquitin-Proteasome System (UPS); drug discovery; lysosomal system; protein degraders
    DOI:  https://doi.org/10.1080/17460441.2023.2187777
  32. Biomed Pharmacother. 2023 Mar 06. pii: S0753-3322(23)00261-5. [Epub ahead of print]161 114473
    Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway.
    Xuechu Wang, Jianping Jia.
      Alzheimer's disease (AD) is the most common neurodegenerative disease. Amyloid-β (Aβ) plaque deposition and apoptosis are main pathological features of AD. Autophagy plays an important role in clearing abnormal protein accumulation and inhibiting apoptosis; however, autophagy defects often occur from the early stages of AD. The serine/threonine AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like kinase 1/2 (ULK1/2) pathway serves as an energy sensor and is involved in autophagy activation. Furthermore, magnolol is an autophagy regulator, and has potential for AD therapy. We propose that magnolol can ameliorate AD pathologies and inhibit apoptosis by regulating autophagy through the AMPK/mTOR/ULK1 pathway. We examined cognitive function and AD-related pathologies in AD transgenic mice and the protective mechanism of magnolol by western blotting, flow cytometry, and a tandem mRFP-GFP-LC3 adenovirus assay in Aβ oligomer (AβO)-induced N2a and BV2 cell models. In our study, magnolol decreased amyloid pathology and ameliorated cognitive impairment in APP/PS1 mice. Moreover, magnolol inhibited apoptosis by downregulating cleaved-caspase-9 and Bax and upregulating Bcl-2 in APP/PS1 mice and AβO-induced cell models. Magnolol promoted autophagy by degrading p62/SQSTM1, and upregulating LC3II and Beclin-1 expression. Magnolol activated the AMPK/mTOR/ULK1 pathway by increasing phosphorylation of AMPK and ULK1 and decreasing mTOR phosphorylation in in vivo and in vitro AD models. AMPK inhibitor weakened the effects of magnolol in promoting autophagy and inhibiting apoptosis, and ULK1 knockdown weakened the effect of magnolol on AβO-induced apoptosis. These results indicate that magnolol inhibits apoptosis and improves AD-related pathologies by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway.
    Keywords:  Alzheimer's disease; Apoptosis; Autophagy; Magnolol
    DOI:  https://doi.org/10.1016/j.biopha.2023.114473
  33. Front Cell Dev Biol. 2023 ;11 1143532
    Protein homeostasis in aging and cancer.
    Xiao-Qiong Chen, Tao Shen, Shao-Jun Fang, Xiao-Min Sun, Guo-Yu Li, Yun-Feng Li.
      Aging is a major risk factor for cancer development. As dysfunction in protein homeostasis, or proteostasis, is a universal hallmark of both the aging process and cancer, a comprehensive understanding of the proteostasis system and its roles in aging and cancer will shed new light on how we can improve health and quality of life for older individuals. In this review, we summarize the regulatory mechanisms of proteostasis and discuss the relationship between proteostasis and aging and age-related diseases, including cancer. Furthermore, we highlight the clinical application value of proteostasis maintenance in delaying the aging process and promoting long-term health.
    Keywords:  aging; autophagy-lysosomal system; cancer; molecular chaperones; protein homeostasis; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3389/fcell.2023.1143532
  34. Nat Rev Endocrinol. 2023 Mar 07.
    The metabolic benefits of exercise-induced hepatic autophagy.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-023-00823-6
  35. Cell Biosci. 2023 Mar 04. 13(1): 44
    Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective.
    Tania B López-Méndez, Miguel Sánchez-Álvarez, Flavia Trionfetti, José L Pedraz, Marco Tripodi, Marco Cordani, Raffaele Strippoli, Juan González-Valdivieso.
      In recent years, progress in nanotechnology provided new tools to treat cancer more effectively. Advances in biomaterials tailored for drug delivery have the potential to overcome the limited selectivity and side effects frequently associated with traditional therapeutic agents. While autophagy is pivotal in determining cell fate and adaptation to different challenges, and despite the fact that it is frequently dysregulated in cancer, antitumor therapeutic strategies leveraging on or targeting this process are scarce. This is due to many reasons, including the very contextual effects of autophagy in cancer, low bioavailability and non-targeted delivery of existing autophagy modulatory compounds. Conjugating the versatile characteristics of nanoparticles with autophagy modulators may render these drugs safer and more effective for cancer treatment. Here, we review current standing questions on the biology of autophagy in tumor progression, and precursory studies and the state-of-the-art in harnessing nanomaterials science to enhance the specificity and therapeutic potential of autophagy modulators.
    Keywords:  Autophagy; Biomaterials; Cancer; Clinical trials; Nanomedicine
    DOI:  https://doi.org/10.1186/s13578-023-00986-9
  36. PLoS Pathog. 2023 Mar;19(3): e1011201
    Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78.
    Da Shi, Ling Zhou, Hongyan Shi, Jiyu Zhang, Jialin Zhang, Liaoyuan Zhang, Dakai Liu, Tingshuai Feng, Miaomiao Zeng, Jianfei Chen, Xin Zhang, Mei Xue, Zhaoyang Jing, Jianbo Liu, Zhaoyang Ji, Haojie He, Longjun Guo, Yang Wu, Jingyun Ma, Li Feng.
      Autophagy plays an important role in the infectious processes of diverse pathogens. For instance, cellular autophagy could be harnessed by viruses to facilitate replication. However, it is still uncertain about the interplay of autophagy and swine acute diarrhea syndrome coronavirus (SADS-CoV) in cells. In this study, we reported that SADS-CoV infection could induce a complete autophagy process both in vitro and in vivo, and an inhibition of autophagy significantly decreased SADS-CoV production, thus suggesting that autophagy facilitated the replication of SADS-CoV. We found that ER stress and its downstream IRE1 pathway were indispensable in the processes of SADS-CoV-induced autophagy. We also demonstrated that IRE1-JNK-Beclin 1 signaling pathway, neither PERK-EIF2S1 nor ATF6 pathways, was essential during SADS-CoV-induced autophagy. Importantly, our work provided the first evidence that expression of SADS-CoV PLP2-TM protein induced autophagy through the IRE1-JNK-Beclin 1 signaling pathway. Furthermore, the interaction of viral PLP2-TMF451-L490 domain and substrate-binding domain of GRP78 was identified to activate the IRE1-JNK-Beclin 1 signaling pathway, and thus resulting in autophagy, and in turn, enhancing SADS-CoV replication. Collectively, these results not only showed that autophagy promoted SADS-CoV replication in cultured cells, but also revealed that the molecular mechanism underlying SADS-CoV-induced autophagy in cells.
    DOI:  https://doi.org/10.1371/journal.ppat.1011201
  37. Gene. 2023 Mar 05. pii: S0378-1119(23)00180-4. [Epub ahead of print] 147339
    Identification of critical autophagy-related proteins in diabetic retinopathy: A multi-dimensional computational study.
    Dipanka Tanu Sarmah, Sunil Gujjar, Santosh Mathapati, Nandadulal Bairagi, Samrat Chatterjee.
      Diabetic retinopathy (DR) is a common consequence of diabetes mellitus and a primary cause of visual impairment in middle-aged and elderly individuals. DR is susceptible to cellular degradation facilitated by autophagy. In this study, we have employed a multi-layer relatedness (MLR) approach to uncover novel autophagy-related proteins involved in DR. The objective of MLR is to determine the relatedness of autophagic and DR proteins by incorporating both expression and prior-knowledge-based similarities. We constructed a prior knowledge-based network and identified the topologically significant novel disease-related candidate autophagic proteins (CAPs). Then, we evaluated their significance in a gene co-expression and a differentially-expressed gene (DEG) network. Finally, we investigated the proximity of CAPs to the known disease-related proteins. Leveraging this methodology, we identified three crucial autophagy-related proteins, TP53, HSAP90AA1, and PIK3R1, which can influence the DR interactome in various layers of heterogeneity of clinical manifestations. They are strongly related to multiple detrimental characteristics of DR, such as pericyte loss, angiogenesis, apoptosis, and endothelial cell migration, and hence may be used to prevent or delay the progression and development of DR. We evaluated one of the identified targets, TP53, in a cell-based model and found that its inhibition resulted in reduced angiogenesis in high glucose condition required to control DR.
    Keywords:  Autophagy; Diabetic retinopathy; Network topology; Protein-protein interaction network analysis; WGCNA
    DOI:  https://doi.org/10.1016/j.gene.2023.147339
  38. Nat Commun. 2023 Mar 10. 14(1): 1312
    The Skp1-Cullin1-FBXO1 complex is a pleiotropic regulator required for the formation of gametes and motile forms in Plasmodium berghei.
    Ravish Rashpa, Natacha Klages, Domitille Schvartz, Carla Pasquarello, Mathieu Brochet.
      Malaria-causing parasites of the Plasmodium genus undergo multiple developmental phases in the human and the mosquito hosts, regulated by various post-translational modifications. While ubiquitination by multi-component E3 ligases is key to regulate a wide range of cellular processes in eukaryotes, little is known about its role in Plasmodium. Here we show that Plasmodium berghei expresses a conserved SKP1/Cullin1/FBXO1 (SCFFBXO1) complex showing tightly regulated expression and localisation across multiple developmental stages. It is key to cell division for nuclear segregation during schizogony and centrosome partitioning during microgametogenesis. It is additionally required for parasite-specific processes including gamete egress from the host erythrocyte, as well as integrity of the apical and the inner membrane complexes (IMC) in merozoite and ookinete, two structures essential for the dissemination of these motile stages. Ubiquitinomic surveys reveal a large set of proteins ubiquitinated in a FBXO1-dependent manner including proteins important for egress and IMC organisation. We additionally demonstrate an interplay between FBXO1-dependent ubiquitination and phosphorylation via calcium-dependent protein kinase 1. Altogether we show that Plasmodium SCFFBXO1 plays conserved roles in cell division and is also important for parasite-specific processes in the mammalian and mosquito hosts.
    DOI:  https://doi.org/10.1038/s41467-023-36999-8
  39. Int J Hematol Oncol Stem Cell Res. 2022 Oct 01. 16(4): 250-263
    The Question of Survival or Death: What Is the Role of Autophagy in Acute Myeloid Leukemia (AML)?
    Atousa Haghi, Mahnaz Mohammadi Kian, Mahdieh Salemi, Mohammad Reza Eghdami, Mohsen Nikbakht.
      Autophagy plays a critical role in balancing sources of energy in response to harsh conditions and nutrient deprivation. Autophagy allows cells to survive in harsh condition and also serve as a death mechanism. Any dysregulation in autophagy signaling may lead to several disorders. Autophagy has been proposed to explain chemotherapy resistance in acute myeloid leukemia (AML). This signaling pathway can either act as a tumor suppressive function or chemo-resistance mechanism. Conventional chemotherapy drugs enhance apoptosis and indicate clinical benefit, but in some cases, relapse and chemotherapy resistance are observed. In leukemia, autophagy may promote cell survival in response to chemotherapy drugs. Therefore, new strategies by inhibiting or activating autophagy may find a broad application for treating leukemia and may significantly enhance clinical outcomes. In this review, we discussed the dimensional role of autophagy in leukemia.
    Keywords:  Acute myeloid leukemia (AML); Autophagy; Cell survival; Chemoresistance
    DOI:  https://doi.org/10.18502/ijhoscr.v16i4.10883
  40. Autophagy. 2023 Mar 09. 1-2
    A novel role of ATG9A and RB1CC1/FIP200 in mediating cell-death checkpoints to repress TNF cytotoxicity.
    Ying Yang, Daniel J Klionsky.
      TNF (tumor necrosis factor) is an important cytokine that regulates immune responses in response to microbial infection. Two fates can be induced by TNF sensing, including activation of NFKB/NF-κB and cell death, which are mainly regulated by the formation of TNFRSF1A/TNFR1 (TNF receptor superfamily member 1A) complex I and complex II, respectively. Abnormal TNF-induced cell death leads to detrimental outcomes, underlying several human inflammatory diseases. The actions of "protective brakes", or so-called specific "cell death checkpoints", are important to prevent TNF cytotoxicity. A recent study published in Science characterizes novel functions of ATG9A, RB1CC1/FIP200 and TAX1BP1 as components of a previously undiscovered TNF-induced cell death checkpoint, independent of its roles in canonical macroautophagy/autophagy. Notably, this ATG9A-controlled cell-death checkpoint contributes to the prevention of inflammatory skin disease, demonstrating its crucial role in serving as a safeguard against the threat of TNF cytotoxicity.
    Keywords:  Autophagy; ULK1 kinase complex; inflammation; skin disease; tumor necrosis factor
    DOI:  https://doi.org/10.1080/15548627.2023.2187609
  41. Cells. 2023 Feb 26. pii: 746. [Epub ahead of print]12(5):
    Depletion of Paraoxonase 1 (Pon1) Dysregulates mTOR, Autophagy, and Accelerates Amyloid Beta Accumulation in Mice.
    Łukasz Witucki, Hieronim Jakubowski.
      Paraoxonase 1 (PON1), a homocysteine (Hcy)-thiolactone detoxifying enzyme, has been associated with Alzheimer's disease (AD), suggesting that PON1 plays an important protective role in the brain. To study the involvement of PON1 in the development of AD and to elucidate the mechanism involved, we generated a new mouse model of AD, the Pon1-/-xFAD mouse, and examined how Pon1 depletion affects mTOR signaling, autophagy, and amyloid beta (Aβ) accumulation. To elucidate the mechanism involved, we examined these processes in N2a-APPswe cells. We found that Pon1 depletion significantly downregulated Phf8 and upregulated H4K20me1; mTOR, phospho-mTOR, and App were upregulated while autophagy markers Bcln1, Atg5, and Atg7 were downregulated at the protein and mRNA levels in the brains of Pon1─/─5xFAD vs. Pon1+/+5xFAD mice. Pon1 depletion in N2a-APPswe cells by RNA interference led to downregulation of Phf8 and upregulation of mTOR due to increased H4K20me1-mTOR promoter binding. This led to autophagy downregulation and significantly increased APP and Aβ levels. Phf8 depletion by RNA interference or treatments with Hcy-thiolactone or N-Hcy-protein metabolites similarly increased Aβ levels in N2a-APPswe cells. Taken together, our findings define a neuroprotective mechanism by which Pon1 prevents Aβ generation.
    Keywords:  APP; H4K20me1; N2a-APPswe cells; Phf8; Pon1; Pon1−/−5xFAD mouse model; amyloid beta; autophagy; homocysteine thiolactone; mTOR
    DOI:  https://doi.org/10.3390/cells12050746
  42. Osteoarthritis Cartilage. 2023 Mar 07. pii: S1063-4584(23)00700-8. [Epub ahead of print]
    Defective Chaperone-mediated Autophagy is a Hallmark of Joint Disease in Patients with Knee Osteoarthritis.
    Irene Lorenzo-Gómez, Uxía Nogueira-Recalde, Christian García-Domínguez, Natividad Oreiro, Martin Lotz, Jose A Pinto-Tasende, Francisco J Blanco, Beatriz Caramés.
       OBJECTIVE: Defects in autophagy contribute to joint aging and Osteoarthritis (OA). Identifying specific autophagy types could be useful for developing novel treatments for OA.
    DESIGN: An autophagy-related gene array was performed in blood from non-OA and knee OA subjects from the Prospective Cohort of A Coruña (PROCOAC). The differential expression of candidate genes was confirmed in blood and knee cartilage and a regression analysis was performed adjusting for age and BMI. HSP90A, a chaperone mediated autophagy (CMA) marker was validated in human knee joint tissues, as well as, in mice with aging-related and surgically-induced OA. The consequences of HSP90AA1 deficiency were evaluated on OA pathogenesis. Finally, the contribution of CMA to homeostasis was studied by assessing the capacity to restore proteostasis upon ATG5-mediated macroautophagy deficiency and genetic HSP90AA1 overexpression.
    RESULTS: 16 autophagy-related genes were significantly down-regulated in blood from knee OA subjects. Validation studies showed that HSP90AA1 was down-regulated in blood and human OA cartilage and correlated with risk incidence of OA. Moreover, HSP90A was reduced in human OA joints tissues and with aging and OA in mice. HSP90AA1 knockdown was linked to defective macroautophagy, inflammation, oxidative stress, senescence and apoptosis. However, macroautophagy deficiency increased CMA, highlighting the CMA-macroautophagy crosstalk. Remarkably, CMA activation was sufficient to protect chondrocytes from damage.
    CONCLUSIONS: We show that HSP90A is a key chaperone for chondrocyte homeostasis, while defective CMA contributes to joint damage. We propose that CMA deficiency is a relevant disease mechanism and could represent a therapeutic target for OA.
    Keywords:  Aging; Chaperone Mediated Autophagy; Chondrocytes; Macroautophagy; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.joca.2023.02.076
  43. Neuroscientist. 2023 Mar 09. 10738584231154551
    Tau, RNA, and RNA-Binding Proteins: Complex Interactions in Health and Neurodegenerative Diseases.
    Evan Lester, Roy Parker.
      The tau protein is a key contributor to multiple neurodegenerative diseases. The pathology of tau is thought to be related to tau's propensity to form self-templating fibrillar structures that allow tau fibers to propagate in the brain by prion-like mechanisms. Unresolved issues with respect to tau pathology are how the normal function of tau and its misregulation contribute to disease, how cofactors and cellular organelles influence the initiation and propagation of tau fibers, and determining the mechanism of tau toxicity. Herein, we review the connection between tau and degenerative diseases, the basis for tau fibrilization, and how that process interacts with cellular molecules and organelles. One emerging theme is that tau interacts with RNA and RNA-binding proteins, normally and in pathologic aggregates, which may provide insight into alterations in RNA regulation observed in disease.
    Keywords:  Alzheimer; RNA; RNA-binding proteins; frontotemporal dementia; membraneless organelles; neurodegeneration; tau
    DOI:  https://doi.org/10.1177/10738584231154551
  44. bioRxiv. 2023 Feb 02. pii: 2023.02.01.526671. [Epub ahead of print]
    Regional and age-dependent changes in ubiquitination in cellular and mouse models of Spinocerebellar ataxia type 3.
    Haiyang Luo, Sokol V Todi, Henry L Paulson, Maria do Carmo Costa.
      Spinocerebellar ataxia type 3 (SCA3), also known as Machadoâ€"Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in the ATXN3 gene that encodes an expanded tract of polyglutamine (polyQ) in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murine Atxn3 or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed in the cerebellum and brainstem of 7- and 47-week-old Atxn3 knockout and SCA3 transgenic mice, and also in relevant mouse and human cell lines. In older mice, we observed that wild-type ATXN3 impacts the cerebellar levels of K48-Ub proteins. In contrast, pathogenic ATXN3 leads to decreased brainstem abundance of K48-Ub species in younger mice and changes in both cerebellar and brainstem K63-Ub levels in an age-dependent manner: younger SCA3 mice have higher levels of K63-Ub while older mice have lower levels of K63-Ub compared to controls. Human SCA3 neuronal progenitor cells also show a relative increase in K63-Ub proteins upon autophagy inhibition. We conclude that wild-type and mutant ATXN3 differentially impact K48-Ub- and K63-Ub-modified proteins in the brain in a region- and age-dependent manner.
    DOI:  https://doi.org/10.1101/2023.02.01.526671
  45. Biochem Soc Trans. 2023 Mar 09. pii: BST20221305. [Epub ahead of print]
    New discoveries in ER-mitochondria communication.
    Margret Helene Bülow, Julia Sellin.
      The study of endoplasmic reticulum (ER)-mitochondria communication is a vast and expanding field with many novel developments in the past few years. In this mini-review, we focus on several recent publications that identify novel functions of tether complexes, in particular autophagy regulation and lipid droplet biogenesis. We review novel findings that shed light on the role of triple contacts between ER and mitochondria with peroxisomes or lipid droplets as the third player. We also summarize recent findings on the role of ER-mitochondria contacts in human neurodegenerative diseases, which implicate either enhanced or reduced ER-mitochondria contacts in neurodegeneration. Taken together, the discussed studies highlight the need for further research into the role of triple organelle contacts, as well as into the exact mechanisms of increased and decreased ER-mitochondria contacts in neurodegeneration.
    Keywords:  endoplasmic reticulum; mitochondria; neurodegeneration; organelles
    DOI:  https://doi.org/10.1042/BST20221305
  46. Ecotoxicol Environ Saf. 2023 Mar 03. pii: S0147-6513(23)00205-1. [Epub ahead of print]254 114701
    3,4-benzopyrene aggravates myocardial ischemia-reperfusion injury-induced pyroptosis through inhibition of autophagy-dependent NLRP3 degradation.
    Kai-Yu Huang, Shuai Liu, Yong-Wei Yu, Bo-Sen Wu, Zhi-Hui Lin, Chen-Xi Zhu, Dong-Yan Song, Yang-Jing Xue, Kang-Ting Ji.
      Polycyclic aromatic hydrocarbons (PAHs) are produced during combustion of organic matter, such as during cigarette smoking, and they exist widely in the environment. Exposure to 3,4-benzo[a]pyrene (BaP), as the most widely studied PAHs, relates to many cardiovascular diseases. However, the underlying mechanism of its involvement remains largely unclear. In this study, we developed a myocardial ischemia-reperfusion (I/R) injury mouse model and an oxygen and glucose deprivation-reoxygenation H9C2 cell model to evaluate the effect of BaP in I/R injury. After BaP exposure, the expression of autophagy-related proteins, the abundance of NLRP3 inflammasomes, and the degree of pyroptosis were measured. Our results show that BaP aggravates myocardial pyroptosis in a autophagy-dependent manner. In addition, we found that BaP activates the p53-BNIP3 pathway via the aryl hydrocarbon receptor to decrease autophagosome clearance. Our findings present new insights into the mechanisms underlying cardiotoxicity and reveal that the p53-BNIP3 pathway, which is involved in autophagy regulation, is a potential therapeutic target for BaP-induced myocardial I/R injury. Because PAHs are omnipresent in daily life, the toxic effects of these harmful substances should not be underestimated.
    Keywords:  3; 4-Benzopyrene; Autophagy; Myocardial ischemia–reperfusion; Pyroptosis
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.114701
  47. Commun Biol. 2023 Mar 10. 6(1): 255
    Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.
    David M Walter, Amy C Gladstein, Katherine R Doerig, Ramakrishnan Natesan, Saravana G Baskaran, A Andrea Gudiel, Keren M Adler, Jonuelle O Acosta, Douglas C Wallace, Irfan A Asangani, David M Feldser.
      SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling.
    DOI:  https://doi.org/10.1038/s42003-023-04618-3
  48. Angew Chem Int Ed Engl. 2023 Mar 10. e202302364
    Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.
    Mingxing Teng, Jie Jiang, Eric S Wang, Qixiang Geng, Sean T Toenjes, Katherine A Donovan, Nada Mageed, Hong Yue, Radosław P Nowak, Jinhua Wang, Theresa D Manz, Eric S Fischer, Lewis C Cantley, Nathanael Schiander Gray.
      Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy-dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non-lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX-4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated this molecule into TMX-4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and a degradable target, and that TMX-4102 and TMX-4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C.
    Keywords:  PI5P4Kγ; PIP4K2C; degrader; lipid kinase; protein degradation
    DOI:  https://doi.org/10.1002/anie.202302364
  49. Cells. 2023 Mar 06. pii: 819. [Epub ahead of print]12(5):
    Molecular Regulation of Autophagy and Asymmetric Cell Division by Cancer Stem Cell Marker CD133.
    Hideki Izumi, Yasuhiko Kaneko, Akira Nakagawara.
      CD133, also called prominin-1, is widely known as a cancer stem cell marker, and its high expression correlates with a poor prognosis in many cancers. CD133 was originally discovered as a plasma membranous protein in stem/progenitor cells. It is now known that Src family kinases phosphorylate the C-terminal of CD133. However, when Src kinase activity is low, CD133 is not phosphorylated by Src and is preferentially downregulated into cells through endocytosis. Endosomal CD133 then associates with HDAC6, thereby recruiting it to the centrosome via dynein motors. Thus, CD133 protein is now known to localize to the centrosome as endosomes as well as to the plasma membrane. More recently, a mechanism to explain the involvement of CD133 endosomes in asymmetric cell division was reported. Here, we would like to introduce the relationship between autophagy regulation and asymmetric cell division mediated by CD133 endosomes.
    Keywords:  CD133; asymmetric cell division; autophagy; neuroblastoma; β-catenin
    DOI:  https://doi.org/10.3390/cells12050819
  50. Aging (Albany NY). 2023 Feb 24. 15(4): 1039-1051
    RIOK3 promotes mTORC1 activation by facilitating SLC7A2-mediated arginine uptake in pancreatic ductal adenocarcinoma.
    Henan Qin, Rui Sun, Xin Guo, Lei Fang, Mengyuan Xu, Yibin Teng, Ning Zhen, Aman Wang, Jiwei Liu.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis. Reprogramming of amino acid metabolism is one of the characteristics of PDAC, in which arginine metabolism is significantly altered in PDAC cells and is involved in important signaling pathways. Current studies have identified arginine deprivation as a potential strategy for PDAC treatment. In this study, we performed Liquid Chromatograph Mass Spectrometer (LC-MS)-based non-targeted metabolomic analysis on PDAC cell lines with stable Rio Kinase 3 (RIOK3) knockdown and PDAC tissues with different RIOK3 expressions and found that RIOK3 expression was significantly correlated with arginine metabolism in PDAC. Subsequent RNA sequencing (RNA-Seq) and Western blot analysis showed that RIOK3 knockdown significantly inhibited the expression of arginine transporter solute carrier family 7 member 2 (SLC7A2). Further studies revealed that RIOK3 promoted arginine uptake, mechanistic target of rapamycin complex 1 (mTORC1) activation, cell invasion, and metastasis in PDAC cells via SLC7A2. Finally, we found that patients with high expression of both RIOK3 and infiltrating Treg cells had a worse prognosis. Overall, our study found that RIOK3 in PDAC cells promotes arginine uptake and mTORC1 activation through upregulation of SLC7A2 expression, and also provides a new therapeutic target for therapeutic strategies targeting arginine metabolism.
    Keywords:  RIOK3; SLC7A2; Treg; arginine metabolism; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.18632/aging.204528
  51. iScience. 2023 Mar 17. 26(3): 106150
    Lysosomal trafficking of the glucose transporter GLUT1 requires sequential regulation by TXNIP and ubiquitin.
    Susan J Qualls-Histed, Casey P Nielsen, Jason A MacGurn.
      Glucose transporters are gatekeepers of cellular glucose metabolism. Understanding how their activity is regulated can provide insight into mechanisms of glucose homeostasis and diseases arising from dysregulation of glucose transport. Glucose stimulates endocytosis of the human glucose transporter GLUT1, but several important questions remain surrounding the intracellular trafficking itinerary of GLUT1. Here, we report that increased glucose availability triggers lysosomal trafficking of GLUT1 in HeLa cells, with a subpopulation of GLUT1 routed through ESCRT-associated late endosomes. This itinerary requires the arrestin-like protein TXNIP, which interacts with both clathrin and E3 ubiquitin ligases to promote GLUT1 lysosomal trafficking. We also find that glucose stimulates GLUT1 ubiquitylation, which promotes its lysosomal trafficking. Our results suggest that excess glucose first triggers TXNIP-mediated endocytosis of GLUT1 and, subsequently, ubiquitylation to promote lysosomal trafficking. Our findings underscore how complex coordination of multiple regulators is required for fine-tuning of GLUT1 stability at the cell surface.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106150
  52. Arch Pharm Res. 2023 Mar 11.
    Cathepsin B maturation plays a critical role in leptin-induced hepatic cancer cell growth through activation of NLRP3 inflammasomes.
    ThiKem Nguyen, Raut Pawan Kumar, Pil-Hoon Park.
      Leptin, an adipose tissue-derived hormone, exhibits potent tumor promoting effects through various mechanisms. Cathepsin B, a member of the lysosomal cysteine proteases, has been shown to modulate the growth of cancer cells. In this study, we have investigated the role of cathepsin B signaling in leptin-induced hepatic cancer growth. Leptin treatment caused significant increase in the levels of active cathepsin B through the axis of endoplasmic reticulum stress and autophagy induction without significant effects on pre- and pro-forms of cathepsin B. Interestingly, inhibition of cathepsin B signaling by gene silencing or treatment with a selective pharmacological inhibitor (CA-074) prevented leptin-enhanced viability of hepatic cancer cell and suppressed progression of cell cycle, indicating the critical role of cathepsin B in leptin-induced hepatic cancer growth. We have further observed that maturation of cathepsin B is required for NLRP3 inflammasomes activation, which is implicated in the growth of hepatic cancer cell. The crucial roles of cathepsin B maturation in leptin-induced hepatic cancer growth and NLRP3 inflammasomes activation were confirmed in an in vivo HepG2 tumor xenograft model. Taken together, these results demonstrate that cathepsin B signaling plays a pivotal role in leptin-induced hepatic cancer cell growth by activating NLRP3 inflammasomes.
    Keywords:  Autophagy; Cathepsin B; ER stress; Inflammasomes; Leptin
    DOI:  https://doi.org/10.1007/s12272-023-01437-2
  53. Cells. 2023 Mar 06. pii: 812. [Epub ahead of print]12(5):
    Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK.
    Sarah Borkowsky, Maximilian Gass, Azadeh Alavizargar, Johannes Hanewinkel, Ina Hallstein, Pavel Nedvetsky, Andreas Heuer, Michael P Krahn.
      The master kinase LKB1 is a key regulator of se veral cellular processes, including cell proliferation, cell polarity and cellular metabolism. It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK. Activation of AMPK by low energy supply and phosphorylation of LKB1 results in an inhibition of mTOR, thus decreasing energy-consuming processes, in particular translation and, thus, cell growth. LKB1 itself is a constitutively active kinase, which is regulated by posttranslational modifications and direct binding to phospholipids of the plasma membrane. Here, we report that LKB1 binds to Phosphoinositide-dependent kinase (PDK1) by a conserved binding motif. Furthermore, a PDK1-consensus motif is located within the kinase domain of LKB1 and LKB1 gets phosphorylated by PDK1 in vitro. In Drosophila, knockin of phosphorylation-deficient LKB1 results in normal survival of the flies, but an increased activation of LKB1, whereas a phospho-mimetic LKB1 variant displays decreased AMPK activation. As a functional consequence, cell growth as well as organism size is decreased in phosphorylation-deficient LKB1. Molecular dynamics simulations of PDK1-mediated LKB1 phosphorylation revealed changes in the ATP binding pocket, suggesting a conformational change upon phosphorylation, which in turn can alter LKB1's kinase activity. Thus, phosphorylation of LKB1 by PDK1 results in an inhibition of LKB1, decreased activation of AMPK and enhanced cell growth.
    Keywords:  AMPK; LKB1; PDK1; cell proliferation; mTOR
    DOI:  https://doi.org/10.3390/cells12050812
  54. Int J Mol Sci. 2023 Feb 22. pii: 4364. [Epub ahead of print]24(5):
    1α,25(OH)2D3 Promotes the Autophagy of Porcine Ovarian Granulosa Cells as a Protective Mechanism against ROS through the BNIP3/PINK1 Pathway.
    Shiyou Wang, Qichun Yao, Fan Zhao, Wenfei Cui, Christopher A Price, Yifan Wang, Jing Lv, Hong Tang, Zhongliang Jiang.
      Vitamin D (VD) is one of the important nutrients required by livestock; however, VD deficiency is reported to be widespread. Earlier studies have suggested a potential role for VD in reproduction. Studies on the correlation between VD and sow reproduction are limited. The aim of the current study was aimed to determine the role of 1,25-dihydroxy vitamin D3 (1α,25(OH)2D3) on porcine ovarian granulosa cells (PGCs) in vitro to provide a theoretical basis for improving the reproductive efficiency of sows. We used chloroquine (autophagy inhibitor) and reactive oxygen species (ROS) scavenger N-acetylcysteine in conjunction with 1α,25(OH)2D3 to explore the effect on PGCs. The results showed that 10 nM of 1α,25(OH)2D3 increased PGC viability and ROS content. In addition, 1α,25(OH)2D3 induces PGC autophagy according to the gene transcription and protein expression levels of LC3, ATG7, BECN1, and SQSTM1 and promotes the generation of autophagosomes. 1α,25(OH)2D3-induced autophagy affects the synthesis of E2 and P4 in PGCs. We investigated the relationship between ROS and autophagy, and the results showed that 1α,25(OH)2D3-induced ROS promoted PGC autophagy. The ROS-BNIP3-PINK1 pathway was involved in PGC autophagy induced by 1α,25(OH)2D3. In conclusion, this study suggests that 1α,25(OH)2D3 promotes PGC autophagy as a protective mechanism against ROS via the BNIP3/PINK1 pathway.
    Keywords:  1α,25(OH)2D3; ROS; autophagy; porcine granulosa cells; signaling pathway
    DOI:  https://doi.org/10.3390/ijms24054364
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