bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2020–06–28
forty-five papers selected by
Viktor Korolchuk, Newcastle University
  1. Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons.
  2. Phenotypic Screen with TSC-Deficient Neurons Reveals Heat-Shock Machinery as a Druggable Pathway for mTORC1 and Reduced Cilia.
  3. Lysosomal dysfunction-induced autophagic stress in diabetic kidney disease.
  4. Autophagic lipid metabolism sustains mTORC1 activity in TSC-deficient neural stem cells.
  5. Interplay Between Lipid Metabolism and Autophagy.
  6. Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation.
  7. Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability.
  8. Regulating RIPK1: another way in which ULK1 contributes to survival.
  9. mTORC and PKCε in Regulation of Alcohol Use Disorder.
  10. Autophagy/virophagy: a "disposal strategy" to combat COVID-19.
  11. Photodynamic therapy: autophagy and mitophagy, apoptosis and paraptosis.
  12. Stress eating: Autophagy targets nuclear pore complexes.
  13. ERK signalling: a master regulator of cell behaviour, life and fate.
  14. Structure and Dynamics in the ATG8 Family From Experimental to Computational Techniques.
  15. Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms.
  16. Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy.
  17. Fasudil Promotes α-Synuclein Clearance in an AAV-Mediated α-Synuclein Rat Model of Parkinson's Disease by Autophagy Activation.
  18. Differential accumulation of storage bodies with aging defines discrete subsets of microglia in the healthy brain.
  19. The Autophagy Regulator p62 Controls PTEN-Dependent Ciliogenesis.
  20. Role of VPS13, a protein with similarity to ATG2, in physiology and disease.
  21. RNA-Binding Proteins Implicated in Mitochondrial Damage and Mitophagy.
  22. Modeling Neurodevelopmental Deficits in Tuberous Sclerosis Complex with Stem Cell Derived Neural Precursors and Neurons.
  23. Autophagy as a decisive process for cell death.
  24. FoxO directly regulates the expression of TOR/S6K and vitellogenin to modulate the fecundity of the brown planthopper.
  25. Deubiquitinating Enzymes in Parkinson's Disease.
  26. Deadly Encounter: Endosomes Meet Mitochondria to Initiate Apoptosis.
  27. Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects.
  28. H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity.
  29. Role of DRAM1 in mitophagy contributes to preeclampsia regulation in mice.
  30. Amino Acids as Regulators of Cell Metabolism.
  31. LRRK2-Related Parkinson's Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis.
  32. 4-O-methylascochlorin activates autophagy by activating AMPK and suppressing c-Myc in glioblastoma.
  33. Local miRNA-Dependent Translational Control of GABAAR Synthesis during Inhibitory Long-Term Potentiation.
  34. Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling.
  35. Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity.
  36. ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells.
  37. Ubiquitin-mediated regulation of sterol homeostasis.
  38. Autophagy and SARS-CoV-2 infection: Apossible smart targeting of the autophagy pathway.
  39. TIPE1-mediated autophagy suppression promotes nasopharyngeal carcinoma cell proliferation via the AMPK/mTOR signalling pathway.
  40. Trehalose alleviates oxidative stress-mediated liver injury and Mallor-Denk body formation via activating autophagy in mice.
  41. Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease.
  42. Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment.
  43. The Antihistamine Deptropine Induces Hepatoma Cell Death through Blocking Autophagosome-Lysosome Fusion.
  44. Adropin regulates hepatic glucose production via PP2A/AMPK pathway in insulin-resistant hepatocytes.
  45. mTOR Signaling and SREBP Activity Increase FADS2 Expression and Can Activate Sapienate Biosynthesis.
  1. Nat Commun. 2020 Jun 26. 11(1): 3258
    Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons.
    M Catarina Silva, Ghata A Nandi, Sharon Tentarelli, Ian K Gurrell, Tanguy Jamier, Diane Lucente, Bradford C Dickerson, Dean G Brown, Nicholas J Brandon, Stephen J Haggarty.
      Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.
    DOI:  https://doi.org/10.1038/s41467-020-16984-1
  2. Cell Rep. 2020 Jun 23. pii: S2211-1247(20)30760-9. [Epub ahead of print]31(12): 107780
    Phenotypic Screen with TSC-Deficient Neurons Reveals Heat-Shock Machinery as a Druggable Pathway for mTORC1 and Reduced Cilia.
    Alessia Di Nardo, Isadora Lenoël, Kellen D Winden, Alina Rühmkorf, Meera E Modi, Lee Barrett, Ebru Ercan-Herbst, Pooja Venugopal, Robert Behne, Carla A M Lopes, Robin J Kleiman, Mónica Bettencourt-Dias, Mustafa Sahin.
      Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ciliary deficits are associated with neurodevelopmental disorders. Here, we examine whether neuronal cilia are affected in TSC. We show that cortical tubers from TSC patients and mutant mouse brains have fewer cilia. Using high-content image-based assays, we demonstrate that mTORC1 activity inversely correlates with ciliation in TSC1/2-deficient neurons. To investigate the mechanistic relationship between mTORC1 and cilia, we perform a phenotypic screen for mTORC1 inhibitors with TSC1/2-deficient neurons. We identify inhibitors of the heat shock protein 90 (Hsp90) that suppress mTORC1 through regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Pharmacological inhibition of Hsp90 rescues ciliation through downregulation of Hsp27. Our study uncovers the heat-shock machinery as a druggable signaling node to restore mTORC1 activity and cilia due to loss of TSC1/2, and it provides broadly applicable platforms for studying TSC-related neuronal dysfunction.
    Keywords:  17-AGG; Hsp27; Hsp90; TSC; autism; brain; cilia; ciliopathy; mTOR
    DOI:  https://doi.org/10.1016/j.celrep.2020.107780
  3. J Cell Mol Med. 2020 Jun 25.
    Lysosomal dysfunction-induced autophagic stress in diabetic kidney disease.
    Hui Juan Zheng, Xueqin Zhang, Jing Guo, Wenting Zhang, Sinan Ai, Fan Zhang, Yaoxian Wang, Wei Jing Liu.
      The catabolic process that delivers cytoplasmic constituents to the lysosome for degradation, known as autophagy, is thought to act as a cytoprotective mechanism in response to stress or as a pathogenic process contributing towards cell death. Animal and human studies have shown that autophagy is substantially dysregulated in renal cells in diabetes, suggesting that activating autophagy could be a therapeutic intervention. However, under prolonged hyperglycaemia with impaired lysosome function, increased autophagy induction that exceeds the degradative capacity in cells could contribute toward autophagic stress or even the stagnation of autophagy, leading to renal cytotoxicity. Since lysosomal function is likely key to linking the dual cytoprotective and cytotoxic actions of autophagy, it is important to develop novel pharmacological agents that improve lysosomal function and restore autophagic flux. In this review, we first provide an overview of the autophagic-lysosomal pathway, particularly focusing on stages of lysosomal degradation during autophagy. Then, we discuss the role of adaptive autophagy and autophagic stress based on lysosomal function. More importantly, we focus on the role of autophagic stress induced by lysosomal dysfunction according to the pathogenic factors (including high glucose, advanced glycation end products (AGEs), urinary protein, excessive reactive oxygen species (ROS) and lipid overload) in diabetic kidney disease (DKD), respectively. Finally, therapeutic possibilities aimed at lysosomal restoration in DKD are introduced.
    Keywords:  autophagic stress; autophagy; diabetic kidney disease; lysosomal dysfunction
    DOI:  https://doi.org/10.1111/jcmm.15301
  4. Nat Metab. 2019 Nov;1(11): 1127-1140
    Autophagic lipid metabolism sustains mTORC1 activity in TSC-deficient neural stem cells.
    Chenran Wang, Michael A Haas, Fuchun Yang, Syn Yeo, Takako Okamoto, Song Chen, Jian Wen, Pranjal Sarma, David R Plas, Jun-Lin Guan.
      Although mTORC1 negatively regulates autophagy in cultured cells, how autophagy impacts mTORC1 signaling, in particular in vivo, is less clear. Here we show that autophagy supports mTORC1 hyperactivation in NSCs lacking Tsc1, thereby promoting defects in NSC maintenance, differentiation, tumourigenesis, and the formation of the neurodevelopmental lesion of Tuberous Sclerosis Complex (TSC). Analysing mice that lack Tsc1 and the essential autophagy gene Fip200 in NSCs we find that TSC-deficient cells require autophagy to maintain mTORC1 hyperactivation under energy stress conditions, likely to provide lipids via lipophagy to serve as an alternative energy source for OXPHOS. In vivo, inhibition of lipophagy or its downstream catabolic pathway reverses defective phenotypes caused by Tsc1-null NSCs and reduces tumorigenesis in mouse models. These results reveal a cooperative function of selective autophagy in coupling energy availability with TSC pathogenesis and suggest a potential new therapeutic strategy to treat TSC patients.
    Keywords:  autophagy; energy stress; lipid catabolism; mTORC1; neural stem cells; tumorigenesis
    DOI:  https://doi.org/10.1038/s42255-019-0137-5
  5. Front Cell Dev Biol. 2020 ;8 431
    Interplay Between Lipid Metabolism and Autophagy.
    Yangchun Xie, Jingbo Li, Rui Kang, Daolin Tang.
      Autophagy is a self-eating process of using lysosomes to degrade macromolecular substances (e.g., proteins and organelles) that are damaged, degenerated, or aging. Lipid metabolism is the synthesis and degradation of lipids (e.g., triglycerides, steroids, and phospholipids) to generate energy or produce the structural components of cell membranes. There is a complex interplay between lipid metabolism (e.g., digestion, absorption, catabolism, biosynthesis, and peroxidation) and autophagy machinery, leading to the modulation of cell homeostasis, including cell survival and death. In particular, lipid metabolism is involved in the formation of autophagic membrane structures (e.g., phagophores and autophagosomes) during stress. Moreover, autophagy, especially selective autophagy (e.g., lipophagy, ferritinophagy, clockophagy, and mitophagy), promotes lipid catabolism or lipid peroxidation-induced ferroptosis through the degradation of various substances within the cell. A better understanding of the mechanisms of autophagy and possible links to lipid metabolism will undoubtedly promote potential treatments for a variety of diseases.
    Keywords:  autophagy; clockophagy; disease; ferritinophagy; lipid; lipophagy; metabolism; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2020.00431
  6. Sci Rep. 2020 Jun 24. 10(1): 10278
    Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation.
    Justyna Okarmus, Helle Bogetofte, Sissel Ida Schmidt, Matias Ryding, Silvia García-López, Brent James Ryan, Alberto Martínez-Serrano, Poul Hyttel, Morten Meyer.
      Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson's disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. We used such cells to investigate the impact of PARK2 KO on the lysosomal compartment and found a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology with enlarged electron-lucent lysosomes and an increased lysosomal content, which was exacerbated by mitochondrial stress and could be ameliorated by antioxidant treatment. We also found decreased lysosomal enzyme activity and autophagic perturbations, suggesting an impairment of the autophagy-lysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, β-glucocerebrosidase, was increased, suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons and reveal an important new connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41598-020-67091-6
  7. Autophagy. 2020 Jun 23. 1-18
    Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability.
    Eugènia Almacellas, Joffrey Pelletier, Charles Day, Santiago Ambrosio, Albert Tauler, Caroline Mauvezin.
      Lysosomes, as primary degradative organelles, are the endpoint of different converging pathways, including macroautophagy. To date, lysosome degradative function has been mainly studied in interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degradation. Here, we show that mitotic transition also relies on lysosome-dependent degradation, as impairment of lysosomes increases mitotic timing and leads to mitotic errors, thus promoting chromosomal instability. Furthermore, we identified several putative lysosomal targets in mitotic cells. Among them, WAPL, a cohesin regulatory protein, emerged as a novel SQSTM1-interacting protein for targeted lysosomal degradation. Finally, we characterized an atypical nuclear phenotype, the toroidal nucleus, as a novel biomarker for genotoxic screenings. Our results establish lysosome-dependent degradation as an essential event to prevent chromosomal instability.
    ABBREVIATIONS: 3D: three-dimensional; APC/C: anaphase-promoting complex; ARL8B: ADP ribosylation factor like GTPase 8B; ATG: autophagy-related; BORC: BLOC-one-related complex; CDK: cyclin-dependent kinase; CENPE: centromere protein E; CIN: chromosomal instability; ConcA: concanamycin A; CQ: chloroquine; DAPI: 4,6-diamidino-2-penylinole; FTI: farnesyltransferase inhibitors; GFP: green fluorescent protein; H2B: histone 2B; KIF: kinesin family member; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; PDS5B: PDS5 cohesin associated factor B; SAC: spindle assembly checkpoint; PLEKHM2: pleckstrin homology and RUN domain containing M2; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; v-ATPase: vacuolar-type H+-translocating ATPase; WAPL: WAPL cohesion release factor.
    Keywords:  Chromosomal instability; chromosomes segregation; lysosome; mitosis; selective autophagy; toroidal nucleus
    DOI:  https://doi.org/10.1080/15548627.2020.1764727
  8. Autophagy. 2020 Jun 24. 1-3
    Regulating RIPK1: another way in which ULK1 contributes to survival.
    Wenxian Wu, Björn Stork.
      The mammalian ULK1 is the central initiating kinase of bulk and selective macroautophagy/autophagy processes. In the past, both autophagy-relevant and non-autophagy-relevant substrates of this Ser/Thr kinase have been reported. Here, we describe our recent finding that ULK1 also regulates TNF signaling pathways. We find that inhibition of autophagy or specifically ULK1 increases TNF-induced cell death. This autophagy-independent pro-survival function of ULK1 is mediated via the phosphorylation of RIPK1 at Ser357. RIPK1 is the central mediator of pro-inflammatory or pro-death signaling pathways induced by TNF, and ULK1-dependent phosphorylation regulates RIPK1 activation and distribution to different intracellular signaling complexes. Our results indicate that ULK1 exerts a cyto-protective function not only by initiating autophagy, but also by controlling RIPK1-mediated cell death.
    Keywords:  Autophagy; RIPK1; TNF; ULK1; necroptosis; necrosome
    DOI:  https://doi.org/10.1080/15548627.2020.1783110
  9. Mini Rev Med Chem. 2020 Jun 24.
    mTORC and PKCε in Regulation of Alcohol Use Disorder.
    Athirah Hanim, Isa Naina Mohamed, Rashidi M Pakri Mohamed, Srijit Das, Norefrina Shafinaz Md Nor, Rosma Ayu Harun, Jaya Kumar.
      Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake and potentiates alcohol-related cues. Alcohol via upstream kinases like mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and mTORC2 was recently reported to be associated with alcohol seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in pathophysiology of AUD. Mammalian target to rapamycin complex 1 (mTORC1), another form of mTOR complex regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in pathogenesis of AUD.
    Keywords:  PDK-1; PKCε; alcohol use disorder.; mTORC1; mTORC2
    DOI:  https://doi.org/10.2174/1389557520666200624122325
  10. Autophagy. 2020 Jun 24. 1-2
    Autophagy/virophagy: a "disposal strategy" to combat COVID-19.
    Dalibor Mijaljica, Daniel J Klionsky.
      Given the devastating consequences of the current COVID-19 pandemic and its impact on all of us, the question arises as to whether manipulating the cellular degradation (recycling, waste disposal) mechanism known as macroautophagy/autophagy (in particular, the selective degradation of virus particles, termed virophagy) might be a beneficial approach to fight the novel coronavirus, SARS-CoV-2. Knowing that "autophagy can reprocess everything", it seems almost inevitable that, sooner rather than later, a further hypothesis-driven work will detail the role of virophagy as a fundamental "disposal strategy" against COVID-19, yielding most needed therapeutic interventions.
    ABBREVIATIONS: ATG, autophagy-related; CoV/CoVs coronavirus/coronaviruses; COVID-19, coronavirus disease 2019; MERS-CoV, Middle East respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
    Keywords:  Autophagy; coronavirus; disposal; virophagy; virus
    DOI:  https://doi.org/10.1080/15548627.2020.1782022
  11. Autophagy. 2020 Jun 25. 1-4
    Photodynamic therapy: autophagy and mitophagy, apoptosis and paraptosis.
    David Kessel, John J Reiners.
      Macroautophagy/autophagy can play a cytoprotective role after photodynamic damage to malignant cells, depending on the site of subcellular damage initiated by reactive oxygen species. There is evidence for such protection when mitochondria are among the targets. Targeting lysosomes has been reported to be more effective for photokilling, perhaps because autophagy offers no cytoprotection. Photodynamic damage to both lysosomes and mitochondria can, however, markedly enhance the overall level of photokilling. Two mechanisms have been proposed to account for this result. Lysosomal photodamage leads to the release of calcium ions, resulting in the activation of the protease CAPN (calpain). CAPN then cleaves ATG5 to a fragment (tATG5) capable of interacting with mitochondria to enhance pro-apoptotic signals. It has also been proposed that targeting lysosomes for photodynamic damage can impair mitophagy, a process that could mitigate the pro-apoptotic effects of mitochondrial targeting. The level of lysosomal photodamage required for suppression of mitophagy is unclear. The "tATG5 route" involves the catalytic action of CAPN, activated by a degree of lysosomal photodamage barely detectible by a viability assay. ER photodamage can also initiate paraptosis, a death pathway functional even in cell types with impaired apoptosis and apparently unaffected by autophagy.
    ABBREVIATIONS: ALLN: N-acetyl-Leu-Leu-norleucinal (cell-permeable inhibitor of calpain); ATG: autophagy related; BPD: benzoporphyrin derivative (Visudyne); ER: endoplasmic reticulum; EtNBS: 5-ethylamino-9-diethyl-aminobenzo[a]phenothiazinium chloride; MTT: a tetrazolium dye; NPe6: mono N-aspartyl chlorin e6; PDT: photodynamic therapy; ROS: reactive oxygen species.
    Keywords:  Apoptosis; cell death; lysosome; macroautophagy; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2020.1783823
  12. J Cell Biol. 2020 Jul 06. pii: e202006007. [Epub ahead of print]219(7):
    Stress eating: Autophagy targets nuclear pore complexes.
    Angelina Sarah Gross, Martin Graef.
      Lee et al. (2020. Nat. Cell Biol.https://doi.org/10.1038/s41556-019-0459-2) and, in this issue, Tomioka et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.201910063) describe the targeted degradation of nuclear pore complexes (NPCs) by selective autophagy, providing insight into the mechanisms of turnover for individual nucleoporins and entire NPCs.
    DOI:  https://doi.org/10.1083/jcb.202006007
  13. Nat Rev Mol Cell Biol. 2020 Jun 23.
    ERK signalling: a master regulator of cell behaviour, life and fate.
    Hugo Lavoie, Jessica Gagnon, Marc Therrien.
      The proteins extracellular signal-regulated kinase 1 (ERK1) and ERK2 are the downstream components of a phosphorelay pathway that conveys growth and mitogenic signals largely channelled by the small RAS GTPases. By phosphorylating widely diverse substrates, ERK proteins govern a variety of evolutionarily conserved cellular processes in metazoans, the dysregulation of which contributes to the cause of distinct human diseases. The mechanisms underlying the regulation of ERK1 and ERK2, their mode of action and their impact on the development and homeostasis of various organisms have been the focus of much attention for nearly three decades. In this Review, we discuss the current understanding of this important class of kinases. We begin with a brief overview of the structure, regulation, substrate recognition and subcellular localization of ERK1 and ERK2. We then systematically discuss how ERK signalling regulates six fundamental cellular processes in response to extracellular cues. These processes are cell proliferation, cell survival, cell growth, cell metabolism, cell migration and cell differentiation.
    DOI:  https://doi.org/10.1038/s41580-020-0255-7
  14. Front Cell Dev Biol. 2020 ;8 420
    Structure and Dynamics in the ATG8 Family From Experimental to Computational Techniques.
    Valentina Sora, Mukesh Kumar, Emiliano Maiani, Matteo Lambrughi, Matteo Tiberti, Elena Papaleo.
      Autophagy is a conserved and essential intracellular mechanism for the removal of damaged components. Since autophagy deregulation is linked to different kinds of pathologies, it is fundamental to gain knowledge on the fine molecular and structural details related to the core proteins of the autophagy machinery. Among these, the family of human ATG8 proteins plays a central role in recruiting other proteins to the different membrane structures involved in the autophagic pathway. Several experimental structures are available for the members of the ATG8 family alone or in complex with their different biological partners, including disordered regions of proteins containing a short linear motif called LC3 interacting motif. Recently, the first structural details of the interaction of ATG8 proteins with biological membranes came into light. The availability of structural data for human ATG8 proteins has been paving the way for studies on their structure-function-dynamic relationship using biomolecular simulations. Experimental and computational structural biology can help to address several outstanding questions on the mechanism of human ATG8 proteins, including their specificity toward different interactors, their association with membranes, the heterogeneity of their conformational ensemble, and their regulation by post-translational modifications. We here summarize the main results collected so far and discuss the future perspectives within the field and the knowledge gaps. Our review can serve as a roadmap for future structural and dynamics studies of the ATG8 family members in health and disease.
    Keywords:  LIR motif; molecular dynamics; selective autophagy; short linear motifs; structural biology
    DOI:  https://doi.org/10.3389/fcell.2020.00420
  15. Antioxidants (Basel). 2020 Jun 22. pii: E545. [Epub ahead of print]9(6):
    Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms.
    Giuseppe Abbruzzese, Javier Morón-Oset, Sabela Díaz-Castroverde, Nuria García-Font, Cesáreo Roncero, Francisco López-Muñoz, José Luis Marco Contelles, María Jesús Oset-Gasque.
      Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 5' AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy.
    Keywords:  apoptosis; autophagy; brain ischemia; cell signaling; natural antioxidants; neuroprotection; phytoestrogens
    DOI:  https://doi.org/10.3390/antiox9060545
  16. Biomed Pharmacother. 2020 Jun 22. pii: S0753-3322(20)30590-4. [Epub ahead of print]129 110397
    Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy.
    Xiaoqing Hu, Meihui Xia, Jiabin Wang, Huimei Yu, Jiannan Chai, Zejun Zhang, Yupei Sun, Jing Su, Liankun Sun.
      The phosphoinositide 3-kinase (PI3K) /AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently mutated in cancers, leading to increased cell proliferation, migration, and chemoresistance. Currently, a number of small molecule inhibitors of the PI3K/AKT/mTOR signaling pathway have been assessed in preclinical and clinical studies. It has been found that dual PI3K/mTOR inhibitors may inhibit cell proliferation and induce apoptosis in cancers, but the mechanism is still being explored. Therefore, determining the role of dual PI3K/mTOR inhibitors PKI-402 in cancer cells may facilitate overcoming chemoresistance. By referring to a gene database and screening gene sequences, we found that human ovarian cancer epithelial cell lines SKOV3 and A2780 had mutations of the PIK3CA gene, which might be relatively sensitive to dual-targeted PI3K/mTOR inhibitors. In this study, our data indicated that dual PI3K/mTOR inhibitor PKI-402 disrupted the balance of Bcl-2 family proteins by degrading the Mcl-1 protein through autophagy. Moreover, the autophagy receptor protein p62 bound to Mcl-1 through its ubiquitin-associated domain (UBA domain) to participate in the degradation of Mcl-1 through autophagy. This offers hope for the treatment of ovarian cancer patients with mutations of the PI3K/AKT/mTOR pathway.
    Keywords:  Apoptosis; Autophagy; Cell growth; Mcl-1; PI3K/AKT/mTOR; p62
    DOI:  https://doi.org/10.1016/j.biopha.2020.110397
  17. J Parkinsons Dis. 2020 Jun 15.
    Fasudil Promotes α-Synuclein Clearance in an AAV-Mediated α-Synuclein Rat Model of Parkinson's Disease by Autophagy Activation.
    Yu-Jie Yang, Lu-Lu Bu, Cong Shen, Jing-Jie Ge, Shu-Jin He, Hui-Ling Yu, Yi-Lin Tang, Zhao Jue, Yi-Min Sun, Wen-Bo Yu, Chuan-Tao Zuo, Jian-Jun Wu, Jian Wang, Feng-Tao Liu.
       BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, but the disease-modifying therapies focusing on the core pathological changes are still unavailable. Rho-associated protein kinase (ROCK) has been suggested as a promising target for developing neuro-protective therapies in PD.
    OBJECTIVE: We aimed to explore the promotion of α-synuclein (α-syn) clearance in a rat model.
    METHODS: In a rat model induced by unilateral injection of adeno-associated virus of serotype 9 (AAV9) expressing A53T α-syn (AAV9-A53T-α-syn) into the right substantia nigra, we aimed to investigate whether Fasudil could promote α-syn clearance and thereby attenuate motor impairments and dopaminergic deficits.
    RESULTS: In our study, treatment with Fasudil (5 mg/kg rat weight/day) for 8 weeks significantly improved the motor deficits in the Cylinder and Rotarod tests. In the in vivo positron emission tomography imaging with the ligand 18F-dihydrotetrabenazine, Fasudil significantly enhanced the dopaminergic imaging in the injected striatum of the rat model (p < 0.05 vs. vehicle group, p < 0.01 vs. left striatum in Fasudil group). The following mechanistic study confirmed that Fasudil could promote the autophagic clearance of α-Syn by Becline 1 and Akt/mTOR pathways.
    CONCLUSION: Our study suggested that Fasudil, the ROCK2 inhibitor, could attenuate the anatomical and behavioral lesions in the Parkinsonian rat model by autophagy activation. Our results identify Fasudil as a drug with high translational potential as disease-modifying treatment for PD and other synucleinopathies.
    Keywords:  A53T α-synuclein; Fasudil; Parkinson’s disease; macroautophagy; positron emission tomography; vesicular monoamine transporter 2
    DOI:  https://doi.org/10.3233/JPD-191909
  18. Elife. 2020 Jun 24. pii: e57495. [Epub ahead of print]9
    Differential accumulation of storage bodies with aging defines discrete subsets of microglia in the healthy brain.
    Jeremy Carlos Burns, Bunny Cotleur, Dirk M Walther, Bekim Bajrami, Stephen J Rubino, Ru Wei, Nathalie Franchimont, Susan L Cotman, Richard M Ransohoff, Michael Mingueneau.
      To date, microglia subsets in the healthy CNS have not been identified. Utilizing autofluorescence (AF) as a discriminating parameter, we identified two novel microglia subsets in both mice and non-human primates, termed autofluorescence-positive (AF+) and negative (AF-). While their proportion remained constant throughout most adult life, the AF signal linearly and specifically increased in AF+ microglia with age and correlated with a commensurate increase in size and complexity of lysosomal storage bodies, as detected by transmission electron microscopy and LAMP1 levels. Post-depletion repopulation kinetics revealed AF- cells as likely precursors of AF+ microglia. At the molecular level, the proteome of AF+ microglia showed overrepresentation of endolysosomal, autophagic, catabolic, and mTOR-related proteins. Mimicking the effect of advanced aging, genetic disruption of lysosomal function accelerated the accumulation of storage bodies in AF+ cells and led to impaired microglia physiology and cell death, suggestive of a mechanistic convergence between aging and lysosomal storage disorders.
    Keywords:  immunology; inflammation; mouse; neuroscience; rhesus macaque
    DOI:  https://doi.org/10.7554/eLife.57495
  19. Front Cell Dev Biol. 2020 ;8 465
    The Autophagy Regulator p62 Controls PTEN-Dependent Ciliogenesis.
    Hyowon Mun, Eun Ji Lee, Minah Park, Goo Taeg Oh, Jong Hoon Park.
      Autophagy is a catabolic process required for maintaining intracellular energy homeostasis. It eliminates harmful proteins and recycles functional macromolecules back into the cell via cargo breakdown. Autophagy is generally suppressed under fed conditions and induced by serum starvation; therefore, it is considered to be a nutrient-sensing mechanism. Cilia, finger-like organelles harboring multiple receptors along their surface, are energy-sensing structures that are also triggered by serum deprivation. Herein, we verified the effect of autophagy alterations on cilia assembly and the specific underlying mechanisms. Autophagy flux altered either by drugs or autophagy-targeting siRNAs strongly inhibited ciliogenesis, and this inhibition was affected by p62, an autophagy regulator, via Pten/Dvl2/AurKA signaling.
    Keywords:  PTEN; SQSTM1/p62; autophagy; cilia; ciliogenesis
    DOI:  https://doi.org/10.3389/fcell.2020.00465
  20. Curr Opin Genet Dev. 2020 Jun 18. pii: S0959-437X(20)30078-2. [Epub ahead of print]65 61-68
    Role of VPS13, a protein with similarity to ATG2, in physiology and disease.
    Berrak Ugur, William Hancock-Cerutti, Marianna Leonzino, Pietro De Camilli.
      The evolutionarily conserved VPS13 family proteins have been implicated in several cellular processes. Mutations in each of the four human VPS13s cause neurodevelopmental or neurodegenerative disorders. Until recently, the molecular function of VPS13 remained elusive. Genetic, functional and structural studies have now revealed that VPS13 acts at contact sites between intracellular organelles to transport lipids by a novel mechanism: direct transfer between bilayers via a hydrophobic channel that spans its entire rod-like N-terminal half. Predicted similarities to the autophagy protein ATG2 suggested a similar role for ATG2 that has now been confirmed by structural and functional studies. Here, after a brief review of this evidence, we discuss what is known of human VPS13 proteins in physiology and disease.
    DOI:  https://doi.org/10.1016/j.gde.2020.05.027
  21. Front Cell Dev Biol. 2020 ;8 372
    RNA-Binding Proteins Implicated in Mitochondrial Damage and Mitophagy.
    Stylianos Ravanidis, Epaminondas Doxakis.
      The mitochondrial lifecycle comprises biogenesis, fusion and cristae remodeling, fission, and breakdown by the autophagosome. This cycle is essential for maintaining proper cellular function, and inhibition of any of these processes results in deterioration of bioenergetics and swift induction of apoptosis, particularly in energy-craving cells such as myocytes and neurons. Regulation of gene expression is a fundamental step in maintaining mitochondrial plasticity, mediated by (1) transcription factors that control the expression of mitochondrial mRNAs and (2) RNA-binding proteins (RBPs) that regulate mRNA splicing, stability, targeting to mitochondria, and translation. More recently, RBPs have been also shown to interact with proteins modulating the mitochondrial lifecycle. Importantly, misexpression or mutations in RBPs give rise to mitochondrial dysfunctions, and there is strong evidence to support that these mitochondrial impairments occur early in disease development, constituting leading causes of pathogenesis. This review presents key aspects of the molecular network of the disease-relevant RBPs, including transactive response DNA-binding protein 43 (TDP43), fused in sarcoma (FUS), T-cell intracellular antigen 1 (TIA1), TIA-related protein (TIAR), and pumilio (PUM) that drive mitochondrial dysfunction in the nervous system.
    Keywords:  FUS; PUM; RNA-binding proteins; TDP43; TIA1; TIAR; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2020.00372
  22. Adv Neurobiol. 2020 ;25 1-31
    Modeling Neurodevelopmental Deficits in Tuberous Sclerosis Complex with Stem Cell Derived Neural Precursors and Neurons.
    Maria Sundberg, Mustafa Sahin.
      Tuberous sclerosis complex (TSC) is a rare genetic disorder that is caused by mutations in TSC1 or TSC2. TSC is a multi-organ disorder characterized by development of non-malignant cellular overgrowths, called hamartomas, in different organs of the body. TSC is also characterized as a neurodevelopmental disorder presenting with epilepsy and autism, and formation of cortical malformations ("tubers"), subependymal giant cell astrocytomas (SEGAs), and subependymal nodules (SENs) in the patient's brain. In this chapter, we are going to give an overview of neural stem cell and neuronal development in TSC. In addition, we will also describe previously developed animal models of TSC that display seizures, autistic-like behaviors, and neuronal cell abnormalities in vivo, and we will compare them to disease phenotypes detected with human stem cell derived neuronal cells in vitro. We will describe the effects of TSC-mutations in different neural cell subtypes, and discuss the mitochondrial function, autophagy, and synaptic development and functional deficits in the neurons. Finally, we will review utilization of these human TSC-patient derived neuronal models for drug screening to develop new treatment options for the neurological phenotypes seen in TSC patients.
    Keywords:  Astrogliosis; Autism; Epilepsy; Mitochondrion; Neural stem cells; Synaptogenesis; Tuberous sclerosis complex; mTORC1; mTORC2
    DOI:  https://doi.org/10.1007/978-3-030-45493-7_1
  23. Exp Mol Med. 2020 Jun 26.
    Autophagy as a decisive process for cell death.
    Seonghee Jung, Hyeonjeong Jeong, Seong-Woon Yu.
      Autophagy is an intracellular catabolic pathway in which cellular constituents are engulfed by autophagosomes and degraded upon autophagosome fusion with lysosomes. Autophagy serves as a major cytoprotective process by maintaining cellular homeostasis and recycling cytoplasmic contents. However, emerging evidence suggests that autophagy is a primary mechanism of cell death (autophagic cell death, ACD) and implicates ACD in several aspects of mammalian physiology, including tumor suppression and psychological disorders. However, little is known about the physiological roles and molecular mechanisms of ACD. In this review, we document examples of ACD and discuss recent progress in our understanding of its molecular mechanisms.
    DOI:  https://doi.org/10.1038/s12276-020-0455-4
  24. Sci China Life Sci. 2020 Jun 18.
    FoxO directly regulates the expression of TOR/S6K and vitellogenin to modulate the fecundity of the brown planthopper.
    Yi Dong, Weiwen Chen, Kui Kang, Rui Pang, Yipei Dong, Kai Liu, Wenqing Zhang.
      As a conserved transcription factor, FoxO plays a crucial role in multiple physiological processes in vivo, including stress resistance, longevity, growth and reproduction. Previous studies on FoxO have focused on human, mouse, Drosophila melanogaster and Caenorhabditis elegans, while there are few reports on agricultural pests and little is known about how FoxO modulates insect fecundity. In Asia, the brown planthopper (BPH) Nilaparvata lugens (Stål) is one of the most serious pests in rice production and high fecundity is the basis of the outbreak of BPH. Here, using the genome-wide ChIP-seq of NlFoxO in BPH, we found that NlFoxO binds to the promoters of ribosomal proteinS6 kinase (NlS6K) and serine/threonine-protein kinase mTOR (NlTOR) and increases their expression levels. We also found that NlFoxO directly binds to the exon of vitellogenin (NlVg) and has a specific inhibitory effect on its expression. In addition, the number of eggs laid and their hatching rate decreased significantly after injection of NlFoxO double-stranded RNA into BPH adults. Our findings provide direct evidence that FoxO modulates insect fecundity through binding to the promoters of NlS6K, NlTOR and the exon of NlVg and affecting their gene expression in the Vg network.
    Keywords:  ChIP-seq; FoxO; Nilaparvata lugens; bind; fecundity; vitellogenin (Vg)
    DOI:  https://doi.org/10.1007/s11427-019-1734-6
  25. Front Physiol. 2020 ;11 535
    Deubiquitinating Enzymes in Parkinson's Disease.
    Joy Chakraborty, Elena Ziviani.
      Mitochondrial dysfunction and neurodegeneration have been directly correlated in many neurodegenerative disorders. Parkinson's disease (PD) in particular has been extensively studied in this context because of its well-characterized association with mitophagy, a selective type of autophagy that degrades mitochondria. Mitophagy is triggered by ubiquitin modification of proteins residing on the surface of mitochondria. Therefore, mitophagy is subject to suppression by deubiquitination. In recent years, many deubiquitinase enzymes (DUBs) emerged as therapeutic targets to compensate hindered mitophagy in PD. It is reasonable that inhibition of specific DUBs should induce mitophagy by blocking deubiquitination of mitochondrial proteins, although the signaling pathway is not always that linear. The broad aspect suggests that there could be cross talks among DUBs, which may in turn have synergistic effect to rescue the disease progression. In this short review we have highlighted DUBs that hold therapeutic value in the field of neurodegenerative diseases, PD in particular.
    Keywords:  DUBs; Parkinson’s disease; mitophagy; neurodegeneration; ubiquitination
    DOI:  https://doi.org/10.3389/fphys.2020.00535
  26. Dev Cell. 2020 Jun 22. pii: S1534-5807(20)30419-6. [Epub ahead of print]53(6): 619-620
    Deadly Encounter: Endosomes Meet Mitochondria to Initiate Apoptosis.
    Mariella Vicinanza, David C Rubinsztein.
      Mitochondrial outer membrane permeabilization (MOMP) is a crucial event enabling apoptotic cell death. In this issue of Developmental Cell, Wang et al. reveal an interaction contributing to full MOMP execution, which depends on endosomes accumulating on apoptotic mitochondria. This causes mitochondrial lipid alterations that may contribute to functional pore assembly.
    DOI:  https://doi.org/10.1016/j.devcel.2020.05.030
  27. Am J Hum Genet. 2020 Jun 16. pii: S0002-9297(20)30159-2. [Epub ahead of print]
    Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects.
    Kyung-Hee Kim, Eun Pyo Hong, Jun Wan Shin, Michael J Chao, Jacob Loupe, Tammy Gillis, Jayalakshmi S Mysore, Peter Holmans, Lesley Jones, Michael Orth, Darren G Monckton, Jeffrey D Long, Seung Kwak, Ramee Lee, James F Gusella, Marcy E MacDonald, Jong-Min Lee.
      A recent genome-wide association study of Huntington disease (HD) implicated genes involved in DNA maintenance processes as modifiers of onset, including multiple genome-wide significant signals in a chr15 region containing the DNA repair gene Fanconi-Associated Nuclease 1 (FAN1). Here, we have carried out detailed genetic, molecular, and cellular investigation of the modifiers at this locus. We find that missense changes within or near the DNA-binding domain (p.Arg507His and p.Arg377Trp) reduce FAN1's DNA-binding activity and its capacity to rescue mitomycin C-induced cytotoxicity, accounting for two infrequent onset-hastening modifier signals. We also idenified a third onset-hastening modifier signal whose mechanism of action remains uncertain but does not involve an amino acid change in FAN1. We present additional evidence that a frequent onset-delaying modifier signal does not alter FAN1 coding sequence but is associated with increased FAN1 mRNA expression in the cerebral cortex. Consistent with these findings and other cellular overexpression and/or suppression studies, knockout of FAN1 increased CAG repeat expansion in HD-induced pluripotent stem cells. Together, these studies support the process of somatic CAG repeat expansion as a therapeutic target in HD, and they clearly indicate that multiple genetic variations act by different means through FAN1 to influence HD onset in a manner that is largely additive, except in the rare circumstance that two onset-hastening alleles are present. Thus, an individual's particular combination of FAN1 haplotypes may influence their suitability for HD clinical trials, particularly if the therapeutic agent aims to reduce CAG repeat instability.
    Keywords:  ▪▪▪
    DOI:  https://doi.org/10.1016/j.ajhg.2020.05.012
  28. J Neurochem. 2020 Jun 23.
    H63D variant of the homeostatic iron regulator (HFE) gene alters α-synuclein expression, aggregation, and toxicity.
    Yunsung Kim, Mark C Stahl, Xuemei Huang, James R Connor.
      Pathological features of Parkinson's disease include the formation of Lewy bodies containing α-synuclein and the accumulation of iron in the substantia nigra. Previous studies have suggested that iron accumulation contributes to the Parkinson's disease pathology through reactive oxygen species production and accelerated α-synuclein aggregation. The current study examines the effects of commonly occurring H63D variant of the homeostatic iron regulatory (HFE) gene on α-synuclein pathology in cell culture and animal models. H63D HFE expression in SH-SY5Y cells lowered endogenous α-synuclein levels and significantly decreased pre-formed fibril induced α-synuclein aggregation. H63D HFE cells were also protected from pre-formed fibril induced apoptosis. Autophagic flux, a major pathway for α-synuclein clearance, was increased in H63D HFE cells. Expression of REDD1 was elevated and rapamycin treatment was unable to further induce autophagy, indicating mTORC1 inhibition as the main mechanism of autophagy induction. Moreover, siRNA knockdown of REDD1 in H63D HFE cells decreased autophagic flux and increased the sensitivity to PFF mediated toxicity. While iron chelator (deferiprone) treatment rescued WT HFE cells from pre-formed fibril toxicity, it exacerbated or was unable to rescue H63D HFE cells. In the in vivo pre-formed fibril intracranial injection model, H67D Hfe (mouse homolog of the human H63D HFE variant) C57BL/6J × 129 mice showed less α-synuclein aggregation and less decline in motor function compared to WT Hfe. Collectively, this study suggests that H63D HFE variant modifies α-synuclein pathology through the induction of autophagy and has the potential to impact the pathogenesis and treatment response in Parkinson's disease.
    Keywords:  HFE; Parkinson’s disease; deferiprone; iron; α-synuclein
    DOI:  https://doi.org/10.1111/jnc.15107
  29. Mol Med Rep. 2020 Jun 23.
    Role of DRAM1 in mitophagy contributes to preeclampsia regulation in mice.
    Guoqing Chen, Ying Lin, Lu Chen, Fa Zeng, Li Zhang, Yan Huang, Pingping Huang, Lingling Liao, Yuanlan Yu.
      Preeclampsia (PE) is a complication during pregnancy that is diagnosed by a new onset of hypertension and proteinuria. Although the pathogenesis of PE is not fully understood, a growing body of evidence indicates that oxidative stress and mitochondrial dysfunction might contribute to the progression of PE. Therefore, the aim of the present study was to determine the role of mitophagy in mitochondrial dysfunction and oxidative stress in PE, and to evaluate the role of DNA damage‑regulated autophagy modulator 1 (DRAM1) in the development of PE. First, a mouse model of PE induced by hypoxia‑inducible factor 1α was established, and high levels of oxidative stress, apoptosis and mitochondrial dysfunction were found in the placentas of PE mice. Additionally, the placentas of PE mice exhibited decreased mitophagy and significantly decreased DRAM1 expression. To further explore the role of DRAM1 in mitophagy, DRAM1 was overexpressed in the placental tissues of PE mice, and this overexpression effectively improved the symptoms of PE mice and significantly reduced blood lipid and urine protein levels. DRAM1 overexpression also improved mitochondrial function and reduced oxidative stress in the placentas of PE mice. In addition, the overexpression of DRAM1 improved mitochondrial fusion and fission, and enhanced mitophagy. Altogether, these results indicated a key role for DRAM1 in mitophagy that contributed to the regulation of PE. To the best of the authors' knowledge, the present study provided the first evidence of a role for DRAM1 in PE, and offered novel insight into the pathophysiological mechanisms of PE.
    DOI:  https://doi.org/10.3892/mmr.2020.11269
  30. Biochemistry (Mosc). 2020 Apr;85(4): 393-408
    Amino Acids as Regulators of Cell Metabolism.
    S V Nesterov, L S Yaguzhinsky, G I Podoprigora, Ya R Nartsissov.
      In this review, we discuss the principles of regulation and synchronization of metabolic processes in mammalian cells using a two-component model of cell metabolism consisting of a controlling signaling system that regulates major enzymatic cascades and executive metabolic system that directly performs biosynthetic reactions. This approach has allowed us to distinguish two transitional metabolic states (from catabolism to anabolism and vice versa) accompanied by major rearrangements in the signaling system. The signaling system of natural amino acids was selected, because amino acids are involved in both signaling and executive metabolic subsystems of general cell metabolism. We have developed a graphical representation of metabolic events that allowed us to demonstrate the succession of processes occurring in both metabolic subsystems during complete metabolic cycle in a non-dividing cell. An important revealed feature of the amino acid signaling system is that the signaling properties of amino acid are determined not only by their molecular structure, but also by the location within the cell. Four major signaling groups of amino acids have been identified that localize to lysosomes, mitochondria, cytosol, and extracellular space adjacent to the plasma membrane. Although these amino acids groups are similar in the composition, they have different receptors. We also proposed a scheme for the metabolism regulation by amino acids signaling that can serve as a basis for developing more complete spatio-temporal picture of metabolic regulation involving a wide variety of intracellular signaling cascades.
    DOI:  https://doi.org/10.1134/S000629792004001X
  31. Front Neurosci. 2020 ;14 556
    LRRK2-Related Parkinson's Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis.
    Pilar Rivero-Ríos, María Romo-Lozano, Rachel Fasiczka, Yahaira Naaldijk, Sabine Hilfiker.
      Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are associated with both familial and sporadic Parkinson's disease (PD). LRRK2 encodes a large protein comprised of a GTPase and a kinase domain. All pathogenic variants converge on enhancing LRRK2 kinase substrate phosphorylation, and distinct LRRK2 kinase inhibitors are currently in various stages of clinical trials. Although the precise pathophysiological functions of LRRK2 remain largely unknown, PD-associated mutants have been shown to alter various intracellular vesicular trafficking pathways, especially those related to endolysosomal protein degradation events. In addition, biochemical studies have identified a subset of Rab proteins, small GTPases required for all vesicular trafficking steps, as substrate proteins for the LRRK2 kinase activity in vitro and in vivo. Therefore, it is crucial to evaluate the impact of such phosphorylation on neurodegenerative mechanisms underlying LRRK2-related PD, especially with respect to deregulated Rab-mediated endolysosomal membrane trafficking and protein degradation events. Surprisingly, a significant proportion of PD patients due to LRRK2 mutations display neuronal cell loss in the substantia nigra pars compacta in the absence of any apparent α-synuclein-containing Lewy body neuropathology. These findings suggest that endolysosomal alterations mediated by pathogenic LRRK2 per se are not sufficient to cause α-synuclein aggregation. Here, we will review current knowledge about the link between pathogenic LRRK2, Rab protein phosphorylation and endolysosomal trafficking alterations, and we will propose a testable working model whereby LRRK2-related PD may present with variable LB pathology.
    Keywords:  LRRK2; Parkinson’s disease; Rab protein; glucocerebrosidase; lysosomal storage disorder; lysosome; phosphorylation; α-synuclein
    DOI:  https://doi.org/10.3389/fnins.2020.00556
  32. J Biochem Mol Toxicol. 2020 Jun 20. e22552
    4-O-methylascochlorin activates autophagy by activating AMPK and suppressing c-Myc in glioblastoma.
    Soon-Kyung Hwang, Si-Yoon Han, Yun-Jeong Jeong, Junji Magae, Young-Seuk Bae, Young-Chae Chang.
      A prior study identified that 4-O-methylascochlorin (MAC), a methylated derivative of ascochlorin (ASC) from the fungus Ascochyta viciae, activates autophagy in leukemia cells by suppressing c-Myc phosphorylation. However, the effects of MAC on autophagy in other cancer cells remain unknown. In the present study, we demonstrated that MAC activated autophagy in human glioblastoma. MAC increased expression of autophagy-related proteins, such as LC3-II and Beclin-1. Moreover, MAC stimulated AMP-activated protein kinase (AMPK) phosphorylation and suppressed phosphorylation of the mTOR, p70S6K, and 4EBP1. The well-known AMPK activator metformin increased LC3-II levels, which were augmented by MAC cotreatment. AMPK knockdown decreased LC3-II levels and inhibited MAC activation of autophagy. Furthermore, MAC suppression of c-Myc expression activated autophagy. Treatment with the c-MYC inhibitor, 10058-FA, induced autophagy, as did c-Myc small interfering RNA knockdown. These effects were augmented by MAC cotreatment. Taken together, these findings indicated that MAC induces autophagy in human glioblastoma by activating AMPK signaling and inhibiting c-Myc protein expression in human glioblastoma.
    Keywords:  4-O-methylascochlorin; AMPK; autophagy; c-Myc; glioblastoma
    DOI:  https://doi.org/10.1002/jbt.22552
  33. Cell Rep. 2020 Jun 23. pii: S2211-1247(20)30765-8. [Epub ahead of print]31(12): 107785
    Local miRNA-Dependent Translational Control of GABAAR Synthesis during Inhibitory Long-Term Potentiation.
    Dipen Rajgor, Alicia M Purkey, Jennifer L Sanderson, Theresa M Welle, Joshua D Garcia, Mark L Dell'Acqua, Katharine R Smith.
      Molecular mechanisms underlying plasticity at brain inhibitory synapses remain poorly characterized. Increased postsynaptic clustering of GABAA receptors (GABAARs) rapidly strengthens inhibition during inhibitory long-term potentiation (iLTP). However, it is unclear how synaptic GABAAR clustering is maintained to sustain iLTP. Here, we identify a role for miR376c in regulating the translation of mRNAs encoding the synaptic α1 and γ2 GABAAR subunits, GABRA1 and GABRG2, respectively. Following iLTP induction, transcriptional repression of miR376c is induced through a calcineurin-NFAT-HDAC signaling pathway and promotes increased translation and clustering of synaptic GABAARs. This pathway is essential for the long-term expression of iLTP and is blocked by miR376c overexpression, specifically impairing inhibitory synaptic strength. Finally, we show that local de novo synthesis of synaptic GABAARs occurs exclusively in dendrites and in a miR376c-dependent manner following iLTP. Together, this work describes a local post-transcriptional mechanism that regulates inhibitory synaptic plasticity via miRNA control of dendritic protein synthesis.
    Keywords:  GABAARs; GABAergic; HDAC; NFAT; NMDAR; miR376c; miRNA; neuron; synapse
    DOI:  https://doi.org/10.1016/j.celrep.2020.107785
  34. J Clin Invest. 2020 Jun 22. pii: 132513. [Epub ahead of print]
    Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling.
    Catherine R Cochrane, Vijesh Vaghjiani, Anette Szczepny, W Samantha N Jayasekara, Alvaro Gonzalez-Rajal, Kazu Kikuchi, Geoffrey W McCaughan, Andrew Burgess, Daniel J Gough, D Neil Watkins, Jason E Cain.
      Ligand-dependent activation of Hedgehog (Hh) signaling in cancer occurs without mutations in canonical pathway genes. Consequently, the genetic basis of Hh pathway activation in adult solid tumors, such as small-cell lung cancer (SCLC), is unknown. Here we show that combined inactivation of Trp53 and Rb1, a defining genetic feature of SCLC, leads to hypersensitivity to Hh ligand in vitro, and during neural tube development in vivo. This response is associated with the aberrant formation of primary cilia, an organelle essential for canonical Hh signaling through smoothened, a transmembrane protein targeted by small-molecule Hh inhibitors. We further show that loss of both Trp53 and Rb1 disables transcription of genes in the autophagic machinery necessary for the degradation of primary cilia. In turn, we also demonstrate a requirement for Kif3a, a gene essential for the formation of primary cilia, in a mouse model of SCLC induced by conditional deletion of both Trp53 and Rb1 in the adult airway. Our results provide a mechanistic framework for therapeutic targeting of ligand-dependent Hh signaling in human cancers with somatic mutations in both TP53 and RB1.
    Keywords:  Autophagy; Cell Biology; Lung cancer; Oncology
    DOI:  https://doi.org/10.1172/JCI132513
  35. Geroscience. 2020 Jun 23.
    Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity.
    Natalia Mota-Martorell, Mariona Jove, Irene Pradas, Rebeca Berdún, Isabel Sanchez, Alba Naudi, Eloi Gari, Gustavo Barja, Reinald Pamplona.
      Species longevity varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of longevity could converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study focuses on the comparative approach in heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot, and mass spectrometry, respectively. Our results demonstrate (1) the existence of differences in species-specific gene expression and protein content of mTORC1, (2) that the achievement of a high longevity phenotype correlates with decreased and inhibited mTORC1, (3) a decreased content of mTORC1 activators in long-lived animals, and (4) that these differences are independent of phylogeny. Our findings, taken together, support an important role for mTORC1 downregulation in the evolution of long-lived mammals.
    Keywords:  Arginine; FKBP12; Methionine cycle metabolites; PRAS40; Raptor; mTOR
    DOI:  https://doi.org/10.1007/s11357-020-00210-3
  36. Signal Transduct Target Ther. 2019 Jun 28. 4(1): 21
    ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells.
    Didem Sohretoglu, Chao Zhang, Jun Luo, Shile Huang.
      Ganoderma lucidum (G. lucidum) extracts, as dietary supplements, have been found to exert potent anticancer activity, which is attributed to the presence of polysaccharides and triterpenes. However, the molecular mechanism underlying the anticancer action of G. lucidum extracts remains to be investigated. Here, we show that ReishiMax GLp, containing G. lucidum polysaccharides and triterpenes (GLPT), inhibited cell proliferation and induced cell death in human lung cancer cells (A549 and A427) and simultaneously suppressed the signaling pathways of mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2), respectively. Mechanistically, GLPT downregulated the phosphorylation and protein levels of insulin-like growth factor 1 receptor (IGFR) and phosphoinositide 3-kinase (PI3K) as well as the protein level of RAS homolog enriched in brain (Rheb). In addition, GLPT also activated the AMP-activated protein kinase (AMPK) network. This was evidenced by observations that GLPT increased the phosphorylation of AMPKα (T172) and its substrates tuberous sclerosis complex 2 (TSC2, S1387) and regulatory-associated protein of mTOR (raptor, S792). Ectopic expression of dominant-negative AMPKα partially mitigated the inhibitory effect of GLPT on mTORC1, indicating that GLPT inhibits mTORC1 partly by activating AMPK. The results suggest that G. lucidum extracts exert anticancer action at least partly by suppressing mTORC1/2 signaling via activation of AMPK and inhibition of IGFR/PI3K/Rheb in tumor cells.
    DOI:  https://doi.org/10.1038/s41392-019-0056-7
  37. Curr Opin Cell Biol. 2020 Jun 21. pii: S0955-0674(20)30056-9. [Epub ahead of print]65 103-111
    Ubiquitin-mediated regulation of sterol homeostasis.
    Dick J H van den Boomen, Norbert Volkmar, Paul J Lehner.
      Cholesterol is an essential component of mammalian membranes, and its homeostasis is strictly regulated, with imbalances causing atherosclerosis, Niemann Pick disease, and familial hypercholesterolemia. Cellular cholesterol supply is mediated by LDL-cholesterol import and de novo cholesterol biosynthesis, and both pathways are adjusted to cellular demand by the cholesterol-sensitive SREBP2 transcription factor. Cholesterol homeostasis is modulated by a wide variety of metabolic pathways and the ubiquitination machinery, in particular E3 ubiquitin ligases. In this article, we review recent progress in understanding the role of E3 ubiquitin ligases in the metabolic control of cellular sterol homeostasis.
    Keywords:  Cholesterol; E3 ubiquitin ligases; ER associated degradation (ERAD); HMG-CoA reductase; LDL-cholesterol import; RNF145; SCAP; SREBP2; Sterol-induced HMGCR degradation; Ubiquitin-mediated cholesterol homeostasis; gp78
    DOI:  https://doi.org/10.1016/j.ceb.2020.04.010
  38. Virulence. 2020 12;11(1): 805-810
    Autophagy and SARS-CoV-2 infection: Apossible smart targeting of the autophagy pathway.
    Shahla Shojaei, Madhumita Suresh, Daniel J Klionsky, Hagar Ibrahim Labouta, Saeid Ghavami.
      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak resulted in 5,993,317 confirmed cases worldwide with 365,394 confirmed deaths (as of May 29th, 2020, WHO). The molecular mechanism of virus infection and spread in the body is not yet disclosed, but studies on other betacoronaviruses show that, upon cell infection, these viruses inhibit macroautophagy/autophagy flux and cause the accumulation of autophagosomes. No drug has yet been approved for the treatment of SARS-CoV-2 infection; however, preclinical investigations suggested repurposing of several FDA-approved drugs for clinical trials. Half of these drugs are modulators of the autophagy pathway. Unexpectedly, instead of acting by directly antagonizing the effects of viruses, these drugs appear to function by suppressing autophagy flux. Based on the established cross-talk between autophagy and apoptosis, we speculate that over-accumulation of autophagosomes activates an apoptotic pathway that results in apoptotic death of the infected cells and disrupts the virus replication cycle. However, administration of the suggested drugs are associated with severe adverse effects due to their off-target accumulation. Nanoparticle targeting of autophagy at the sites of interest could be a powerful tool to efficiently overcome SARS-CoV-2 infection while avoiding the common adverse effects of these drugs.
    Keywords:  Apoptosis; SARS-CoV-2; autophagy flux; drug targeting; macroautophagy; nanomedicine; nanoparticles
    DOI:  https://doi.org/10.1080/21505594.2020.1780088
  39. J Cell Mol Med. 2020 Jun 25.
    TIPE1-mediated autophagy suppression promotes nasopharyngeal carcinoma cell proliferation via the AMPK/mTOR signalling pathway.
    Yongliang Liu, Xiangqin Qi, Zhenan Zhao, Daoliang Song, Lianqing Wang, Qiaoli Zhai, Xiaoning Zhang, Peiqing Zhao, Xinxin Xiang.
      Recent studies have shown that tumour necrosis factor-α-induced protein 8 like-1(TIPE1) plays distinct roles in different cancers. TIPE1 inhibits tumour proliferation and metastasis in a variety of tumours but acts as an oncogene in cervical cancer. The role of TIPE1 in nasopharyngeal carcinoma (NPC) remains unknown. Interestingly, TIPE1 expression was remarkably increased in NPC tissue samples compared to adjacent normal nasopharyngeal epithelial tissue samples in our study. TIPE1 expression was positively correlated with that of the proliferation marker Ki67 and negatively correlated with patient lifespan. In vitro, TIPE1 inhibited autophagy and induced cell proliferation in TIPE1-overexpressing CNE-1 and CNE-2Z cells. In addition, knocking down TIPE1 expression promoted autophagy and decreased proliferation, whereas overexpressing TIPE1 increased the levels of pmTOR, pS6 and P62 and decreased the level of pAMPK and the LC3B. Furthermore, the decrease in autophagy was remarkably rescued in TIPE1-overexpressing CNE-1 and CNE-2Z cells treated with the AMPK activator AICAR. In addition, TIPE1 promoted tumour growth in BALB/c nude mice. Taken together, results indicate that TIPE1 promotes NPC progression by inhibiting autophagy and inducing cell proliferation via the AMPK/mTOR signalling pathway. Thus, TIPE1 could potentially be used as a valuable diagnostic and prognostic biomarker for NPC.
    Keywords:  AMPK/mTOR signalling pathway; TIPE1; autophagy; cell proliferation; nasopharyngeal carcinoma
    DOI:  https://doi.org/10.1111/jcmm.15550
  40. Med Mol Morphol. 2020 Jun 25.
    Trehalose alleviates oxidative stress-mediated liver injury and Mallor-Denk body formation via activating autophagy in mice.
    Yuichi Honma, Miyuki Sato-Morita, Yuka Katsuki, Hitomi Mihara, Ryoko Baba, Katsuhiko Hino, Akira Kawashima, Toshio Ariyasu, Masaru Harada.
      Autophagy is a degradation pathway for long-lived cytoplasmic proteins or damaged organelles and also for many aggregate-prone and disease-causing proteins. Endoplasmic reticulum (ER) stress and oxidative stress are associated with the pathophysiology of various liver diseases. These stresses induce the accumulation of abnormal proteins, Mallory-Denk body (MDB) formation and apoptosis in hepatocytes. A disaccharide trehalose had been reported to induce autophagy and decrease aggregate-prone proteins and cytotoxicity in neurodegenerative disease models. But the effects of trehalose in hepatocytes have not been fully understood. We examined the effect of trehalose on autophagy, ER stress and oxidative stress-mediated cytotoxicity and MDB formation in hepatocytes using mice model with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment for 3 months. We administered trehalose by intraperitoneal injection of water containing 10% trehalose (0.02 mg/g body weight) every other day for 3 months. Our results demonstrated that trehalose induced autophagy and reduced ER stress, oxidative stress, MDB formation and apoptosis in hepatocytes of DDC-fed mice by Western blotting and immunostaining analyses. Electron microscopy revealed that trehalose induced autolysosome formation, which located is close to the MDBs. Thus, our findings suggest that trehalose can become a therapeutic agent for oxidative stress-related liver diseases via activating autophagy.
    Keywords:  Autophagy; Disaccharide; Endoplasmic reticulum stress; Mallory-Denk body; Mammalian target of rapamycin; Oxidative stress; Trehalose
    DOI:  https://doi.org/10.1007/s00795-020-00258-2
  41. Proc Natl Acad Sci U S A. 2020 Jun 24. pii: 202002144. [Epub ahead of print]
    Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease.
    Manish Sharma, Sumitha Rajendrarao, Neelam Shahani, Uri Nimrod Ramírez-Jarquín, Srinivasa Subramaniam.
      Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine of huntingtin (mHTT). mHTT is ubiquitously present, but it induces noticeable damage to the brain's striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling revealed that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. Moreover, the protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. Depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy in HD cells. In contrast, reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Ribosome profiling also revealed that LC3A and LC3B, the two major autophagy initiators, show altered ribosome occupancy in HD cells. We also detected the presence of numerous micronuclei, which are known to induce cGAS, in the cytoplasm of neurons derived from human HD embryonic stem cells. Collectively, our results indicate that cGAS is up-regulated in HD and mediates inflammatory and autophagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.
    Keywords:  HTT-copy number; autophagy flux; cotranslational cleavage; pro-inflammatory response; striatal vulnerability
    DOI:  https://doi.org/10.1073/pnas.2002144117
  42. EMBO J. 2020 Jun 22. e103790
    Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment.
    Anaelle A Dumas, Nicola Pomella, Gabriel Rosser, Loredana Guglielmi, Claire Vinel, Thomas O Millner, Jeremy Rees, Natasha Aley, Denise Sheer, Jun Wei, Anantha Marisetty, Amy B Heimberger, Robert L Bowman, Sebastian Brandner, Johanna A Joyce, Silvia Marino.
      Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.
    Keywords:   TAM ; mTOR ; T cells; glioblastoma; microglia
    DOI:  https://doi.org/10.15252/embj.2019103790
  43. Cancers (Basel). 2020 Jun 18. pii: E1610. [Epub ahead of print]12(6):
    The Antihistamine Deptropine Induces Hepatoma Cell Death through Blocking Autophagosome-Lysosome Fusion.
    Yu-Chih Liang, Chi-Ching Chang, Ming-Thau Sheu, Shyr-Yi Lin, Chia-Chen Chung, Chang-Ting Teng, Fat-Moon Suk.
      Some antihistamines have exhibited significant antitumor activity alone or in combination with other therapies in in vitro and clinical studies. However, the underlying mechanisms of how antihistamines inhibit hepatocellular carcinoma proliferation are still unknown. We first screened the antiproliferation activity of 12 benzocycloheptene structural-analogue drugs, and results showed that deptropine was the most potent inhibitor of both Hep3B and HepG2 human hepatoma cells. Deptropine significantly increased light chain 3B-II (LC3B-II) expression but did not induce sequestosome 1 (SQSTM1/p62) degradation in either cell line. Interestingly, other autophagy-related proteins, such as autophagy-related 7 (ATG7), vacuolar protein sorting 34 (VPS34), phosphorylated adenosine 5'-monophosphate-activated protein kinase (AMPK), and phosphorylated protein kinase B (PKB, also known as Akt), exhibited no significant change in either deptropine-treated cell line. Deptropine also inhibited the processing of cathepsin L from its precursor form to its mature form. Immunofluorescence microscopy showed an increase of autophagosomes in deptropine-treated cells, but deptropine blocked the fusion between autophagosomes and lysosomes. In a xenograft nude mice model, 2.5 mg/kg deptropine showed a great inhibitory effect on Hep3B tumor growth. These results suggest that deptropine can induce in vitro and in vivo hepatoma cell death, and the underlying mechanisms might be mediated through inhibiting autophagy by blocking autophagosome-lysosome fusion.
    Keywords:  LC3B; SQSTM1/p62; antihistamine; autophagy; deptropine; hepatoma
    DOI:  https://doi.org/10.3390/cancers12061610
  44. FASEB J. 2020 Jun 24.
    Adropin regulates hepatic glucose production via PP2A/AMPK pathway in insulin-resistant hepatocytes.
    Xu Chen, Shen Chen, Tianran Shen, Wenqi Yang, Qian Chen, Peiwen Zhang, Yiran You, Xiaoyuan Sun, Huihui Xu, Yi Tang, Jiaxin Mi, Yan Yang, Wenhua Ling.
      Adropin as a secretory peptide has shown a protective role on the disorders of glucose and lipid metabolism. However, the role and mechanism of this peptide on the hepatic glucose production has remained unclear. Adropin knockout (KO) mice were generated to explore its effects on the enhanced hepatic glucose production in obesity. We found that compared to wild-type (WT) mice, adropin-KO mice developed the unbalanced enhanced hepatic glucose production in advance of the whole-body insulin resistance (IR) by high-fat diet (HFD). Mechanistically, adropin dissociated CREB-CRTC2 and FoxO1-PGC1α complex and reduced their binding to the promoters of G6Pase and PEPCK to decrease glucose production in IR. However, these effects were not observed in insulin-sensitive hepatocytes. Furthermore, in IR hepatocytes, dampened AMPK signaling was re-activated by adropin treatment via inhibition of PP2A. To further authenticate AMPK role in vivo, we administrated HFD-fed mice with AAV8-CA AMPKα and found that AMPK activation functionally restored the aberrant glucose production and IR induced by adropin-deficiency. This study provides evidence that adropin activates the AMPK pathway via inhibition of PP2A and decreases the liver glucose production in IR context. Therefore, adropin may represent a novel target for the prevention and treatment of diabetes.
    Keywords:  AMPK; diabetes; gluconeogenesis; obesity
    DOI:  https://doi.org/10.1096/fj.202000115RR
  45. Cell Rep. 2020 Jun 23. pii: S2211-1247(20)30787-7. [Epub ahead of print]31(12): 107806
    mTOR Signaling and SREBP Activity Increase FADS2 Expression and Can Activate Sapienate Biosynthesis.
    Mouna Triki, Gianmarco Rinaldi, Melanie Planque, Dorien Broekaert, Alina M Winkelkotte, Carina R Maier, Sudha Janaki Raman, Anke Vandekeere, Joke Van Elsen, Martin F Orth, Thomas G P Grünewald, Almut Schulze, Sarah-Maria Fendt.
      Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Conversely, inhibiting mTOR signaling decreases FADS2 expression and sapienate biosynthesis in MEFs with Tsc2 deletion, HUH7 hepatocellular carcinoma cells, and orthotopic HUH7 liver xenografts. In conclusion, we show that mTOR signaling and SREBP activity are sufficient to activate sapienate metabolism by increasing FADS2 expression. Consequently, targeting mTOR signaling can reduce sapienate metabolism in vivo.
    Keywords:  FADS2; SCD1; SREBP; cancer; fatty acid metabolism; glioblastoma; hepatocellular carcinoma; mTOR; palmitate; palmitoleate; sapienate
    DOI:  https://doi.org/10.1016/j.celrep.2020.107806
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