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| Open AccessPhase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates
How phase separation participates in mitophagy remains unclear. Here the authors show that Nur77 and p62/SQSTM1 through “head-to-head” and “tail-to-tail” interactions form membraneless condensates capable of sequestering dysfunctional mitochondria and tethering them to autolysosome for degradation.
- Shuang-zhou Peng
- , Xiao-hui Chen
- & Xiao-kun Zhang
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Article
| Open AccessPGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones
Degradation of misfolded proteins from the endoplasmic reticulum (ER) is important for maintaining proper cellular protein homeostasis. Here, the authors discovered that the ER membrane protein PGRMC1 binds to misfolded prohormones for recruitment into the ER-phagy degradative pathway.
- Yu-Jie Chen
- , Jeffrey Knupp
- & Billy Tsai
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Article
| Open AccessOPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection
During herpesvirus infection, most individuals intrinsically suppress a primary infection and therewith preclude potential damage or neurodegeneration of the CNS. Here, Ames et al. show that Optineurin (OPTN), a conserved autophagy receptor, restricts HSV-1 spread, degrades viral VP16 through autophagy and is neuroprotective against HSV infection in vivo.
- Joshua Ames
- , Tejabhiram Yadavalli
- & Deepak Shukla
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| Open AccessReconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation
Misfolded proteins are ubquitinated and subsequently condensed by cargo receptors for selective autophagy. Here, the authors use in vitro reconstitution to elegantly dissect how the receptors p62/SQSTM1, NBR1 and TAX1BP1 contribute to p62-ubiquitin condensate formation and degradation by autophagy.
- Eleonora Turco
- , Adriana Savova
- & Sascha Martens
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| Open AccessStress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion
Glucocorticoids are associated with stress. Here, the authors show that high levels of glucocorticoid stress promote secretory autophagy of matrix metalloproteinase 9 via a stress responsive chaperone, increasing brain-derived neurotrophic factor processing and potentially altering adult synaptic plasticity.
- Silvia Martinelli
- , Elmira A. Anderzhanova
- & Nils C. Gassen
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Article
| Open AccessGαq activation modulates autophagy by promoting mTORC1 signaling
Nutrient status in the cell regulates autophagy via mTORC1 activity. Here, the authors show that the ubiquitous G protein subunit Gαq contributes to nutrient sensing by promoting formation of an mTOR-p62-Raptor complex in replete conditions, modulating autophagy.
- Sofía Cabezudo
- , Maria Sanz-Flores
- & Catalina Ribas
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Article
| Open AccessTGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy
Uncontrolled activation of fibroblasts contributes to tissue fibrosis and organ dysfunction. Here the authors demonstrate that the epigenetic control of autophagy is disturbed by a TGFβ-dependent downregulation of MYST1 in systemic sclerosis patients. Restoration of the epigenetic control of autophagy reduces fibroblast activation and ameliorates fibrotic tissue remodeling.
- Ariella Zehender
- , Yi-Nan Li
- & Jörg H. W. Distler
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Article
| Open AccessVCP maintains nuclear size by regulating the DNA damage-associated MDC1–p53–autophagy axis in Drosophila
Cells maintain a constant cytoplasm to nucleus volume ratio, although the role of DNA damage is not well explored. Here, the authors use Drosophila to connect TER94, the fly homolog of VCP, to disruption of DNA damage repair, leading to ubiquitinated Mu2 protein accumulation and enlarged nuclei.
- Ya-Chu Chang
- , Yu-Xiang Peng
- & Tzu-Kang Sang
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Article
| Open AccessThbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy
Beneficial and detrimental effects have been ascribed to the different Thrombospondin (Thbs) proteins in the adult mammalian heart. Here, the authors show that Thbs1-mediated activation of PERK-eIF2α-ATF4-induced autophagy regulates adult cardiomyocyte size in the stressed heart.
- Davy Vanhoutte
- , Tobias G. Schips
- & Jeffery D. Molkentin
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Article
| Open AccessCIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
Age-related macular degeneration (AMD) has been connected to deficits in autophagy. Here, the authors demonstrate, in mice and dry-AMD patient samples, that calcium and integrin binding protein 2 (CIB2) regulates Rheb-mTORC1 signaling axis, and subsequently autophagy.
- Saumil Sethna
- , Patrick A. Scott
- & Zubair M. Ahmed
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| Open AccessSARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals
Viruses manipulate host cell pathways to support infection. Here the authors show that SARS-CoV-2 infection modulates cellular metabolism and limits autophagy, and identify druggable host pathways for virus inhibition.
- Nils C. Gassen
- , Jan Papies
- & Marcel A. Müller
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Article
| Open AccessNEK9 regulates primary cilia formation by acting as a selective autophagy adaptor for MYH9/myosin IIA
Ciliogenesis is a tightly regulated process, although the role of selective autophagy is unclear. Here, the authors show NIMA-related kinase 9 controls actin network stabilization and subsequently ciliogenesis by targeting myosin MYH9 for autophagic degradation via GABARAP interaction.
- Yasuhiro Yamamoto
- , Haruka Chino
- & Noboru Mizushima
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Article
| Open AccessModel-based analysis uncovers mutations altering autophagy selectivity in human cancer
Although autophagy has been linked to tumourigenesis, it is unclear how genomic alterations affect autophagy selectivity in tumours. Here, the authors establish a pipeline that integrates computational and experimental approaches to show that altered autophagy selectivity is frequent in cancer cells and link glycogen autophagy with tumourigenesis.
- Zhu Han
- , Weizhi Zhang
- & Da Jia
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Article
| Open AccessThe P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2
The role of endothelial copper transporter ATP7A in vascular function and angiogenesis remains largely unexplored. Here the authors show that ATP7A promotes VEGFR2 signaling and angiogenesis by limiting autophagy-mediated degradation of VEGFR2, which enhances reparative neovascularization.
- Dipankar Ash
- , Varadarajan Sudhahar
- & Masuko Ushio-Fukai
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Article
| Open AccessOverarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
Members of the CHD chromatin remodeler family are implicated in human pathologies, however CHD6 remained poorly studied. Here, the authors show that CHD6 binds to and regulates autophagy and stress response genes across cell types. They identify a clinical mutation that affects its ability to recruit cofactors, leading to impaired autophagy induction and DNA repair.
- Yulia Kargapolova
- , Rizwan Rehimi
- & Argyris Papantonis
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Article
| Open AccessCardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover
Decreased expression of BAG3 in the heart is associated with contractile dysfunction and heart failure. Here the authors show that this is due to decreased BAG3-dependent sarcomere protein turnover, which impairs mechanical function, and that sarcomere force-generating capacity is restored with BAG3 gene therapy.
- Thomas G. Martin
- , Valerie D. Myers
- & Jonathan A. Kirk
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Article
| Open AccessMAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells
Haematopoietic stem cells (HSCs) are metabolically quiescent, with balanced myeloid and lymphoid potential. Here the authors show that MAEA is required in HSCs for ubiquitination and downregulation of surface cytokine receptors via autophagy; MAEA loss leads to impaired HSC quiescence and a myeloproliferative disorder.
- Qiaozhi Wei
- , Sandra Pinho
- & Paul S. Frenette
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Article
| Open AccessVPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics
Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.
- Cajsa Davegårdh
- , Johanna Säll
- & Charlotte Ling
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Article
| Open AccessSelectivity of mRNA degradation by autophagy in yeast
Autophagic degradation of proteins and organelles is well studied, but the role of autophagy in RNA regulation is unclear. Here, the authors profile mRNAs targeted to the vacuole in yeast and observe autophagy-mediated mRNA degradation is not random but rather is a preferential process.
- Shiho Makino
- , Tomoko Kawamata
- & Yoshinori Ohsumi
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Article
| Open AccessAcetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
The tau protein has been implicated in neurodegenerative disorders and can propagate from cell to cell. Here, the authors show that tau acetylation reduces its degradation by chaperone-mediated autophagy, causing re-routing to other autophagic pathways and increasing extracellular tau release.
- Benjamin Caballero
- , Mathieu Bourdenx
- & Ana Maria Cuervo
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Article
| Open AccessUXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy
p62/SQSTM1 acts as a key mediator in the selective autophagy of protein aggregates, or aggrephagy. Here the authors identify the prefoldin-like chaperone UXT as an autophagy adaptor of p62 dependent aggrephagy and show that ectopic UXT expression delays motor neuron degeneration in a Xenopus model.
- Min Ji Yoon
- , Boyoon Choi
- & Chungho Kim
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Article
| Open AccessThe decrease of intraflagellar transport impairs sensory perception and metabolism in ageing
Sensory perception and metabolic homeostasis are known to deteriorate with ageing, while mechanisms underlying their deterioration remain poorly understood. Here, the authors demonstrate that decrease of intraflagellar transport in the cilia of sensory neurons impairs sensory perception and metabolism in ageing C. elegans.
- Yincong Zhang
- , Xiaona Zhang
- & Yidong Shen
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Article
| Open Accessα-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation
Autophagy regulates multiple pathways including YAP/TAZ of the Hippo pathway, but precise mechanisms are unclear as autophagy may either activate or inhibit YAP/TAZ. Here, the authors show that autophagy can either activate or regulate YAP/TAZ via dynamic negative feedback loops involving alpha-catenin.
- Mariana Pavel
- , So Jung Park
- & David C. Rubinsztein
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Article
| Open AccessPhosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation
Cooperation between the ULK complex and autophagy receptors mediates targeting cargoes to autophagosomes. Here, the authors show that interactions of ULK subunit FIP200 with autophagy receptors CCPG1 and Optineurin can be regulated by phosphorylation, suggesting a general binding mode shared by autophagy receptors.
- Zixuan Zhou
- , Jianping Liu
- & Lifeng Pan
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Article
| Open AccessStructural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes
The phosphatidylinositol-3-phosphate (PI3P) is generated by the lipid kinase VPS34, in the context of VPS34 complex I on autophagosomes or complex II on endosomes. Biochemical and structural analyses provide insights into the mechanism of both VPS34 complexes recruitment to and activation on membranes by specific Rab GTPases.
- Shirley Tremel
- , Yohei Ohashi
- & Roger L. Williams
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Article
| Open AccessOxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation
LC3-associated phagocytosis (LAP) is a non-canonical use of the autophagy machinery that can contribute to immune responses. Here, the authors describe the mechanism by which ROS production regulates LAPosome stabilization sustaining MHC II dependent antigen presentation.
- Laure-Anne Ligeon
- , Maria Pena-Francesch
- & Christian Münz
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Article
| Open AccessVPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism
Autophagy and the ubiquitin–proteasome system (UPS) are cellular quality control processes, but their coordination remains unclear. Here, the authors show that branched ubiquitination of VPS34 functions as a switch between UPS and autophagy and has an important role in lipid metabolism in the liver.
- Yu-Hsuan Chen
- , Tzu-Yu Huang
- & Ruey-Hwa Chen
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Article
| Open AccessMetabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation
Pyruvate kinase phosphorylates histone H3T11 (H3pT11) and represses gene expression by forming a large complex SESAME (Serine-responsive SAM-containing Metabolic Enzyme). Here the authors show that SESAME-catalyzed H3pT11 regulates telomere silencing by promoting Sir2 binding at telomeres and preventing autophagy-mediated Sir2 degradation.
- Shihao Zhang
- , Xilan Yu
- & Shanshan Li
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Article
| Open AccessBNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects
Stress-induced glucocorticoids cause mitochondrial damage in neurons, but they are not cleared by mitophagy. Here, the authors show that glucocorticoids inhibit NIX-dependent basal mitophagy, contributing to neurodegeneration in a mouse model that can be reversed by pretreatment with a NIX enhancer.
- Gee Euhn Choi
- , Hyun Jik Lee
- & Ho Jae Han
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Article
| Open AccessEndonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response
The role of Endonuclease G in autophagy remains unclear. Here the authors report that ENDOG is released from mitochondria during starvation and promotes autophagy by suppressing mTOR signaling and activating DNA damage response.
- Wenjun Wang
- , Jianshuang Li
- & Qinghua Zhou
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Article
| Open AccessAn autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer
Islet amyloid polypeptide (IAPP) deposition is associated with islet cell loss in diabetes. Here the authors show that a small molecule autophagy enhancer reduces IAPP accumulation in vitro, and also improves glucose tolerance in hIAPP+ mice fed high-fat diet, accompanied by reduced hIAPP accumulation, in vivo.
- Jinyoung Kim
- , Kihyoun Park
- & Myung-Shik Lee
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Article
| Open Accessp62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response
Liquid-liquid phase separation of p62/SQSTM1 has been previously described, although the significance in vivo remains unclear. Here the authors show p62 droplets contain ubiquitin, autophagy-related proteins and Keap1 to serve as platform of not only autophagosome formation but also Nrf2 activation.
- Shun Kageyama
- , Sigurdur Runar Gudmundsson
- & Masaaki Komatsu
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Article
| Open AccessAutophagy sustains glutamate and aspartate synthesis in Saccharomyces cerevisiae during nitrogen starvation
Autophagy is known to promote cellular survival upon starvation, although how recycled components fit into cellular metabolism has not been well established. Here, the authors show in yeast that autophagy tunes cellular metabolism based on nitrogen availability via glutamate and aspartate synthesis.
- Kuanqing Liu
- , Benjamin M. Sutter
- & Benjamin P. Tu
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Article
| Open AccessRegulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain
The WD40 domain of ATG16L1 is thought to be involved in non-canonical autophagy. Here the authors screen peptide libraries and identify interactions between this domain and the IL-2Rγ and IL-10RB receptors, indicating endosomal regulation of cytokine signalling by non-canonical autophagy.
- Inmaculada Serramito-Gómez
- , Emilio Boada-Romero
- & Felipe X. Pimentel-Muiños
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Article
| Open AccessPharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model
Previous work suggests that mitophagy in neurons is could be therapeutic in Alzheimer’s disease (AD). Here, the authors screen a library of drugs and identify UMI-77, a mitophagy inducer with beneficial effects in an AD mouse model, by binding MCL-1, which they identify as a mitophagy receptor.
- Xufeng Cen
- , Yanying Chen
- & Hongguang Xia
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Article
| Open AccessWipi3 is essential for alternative autophagy and its loss causes neurodegeneration
Unlike canonical macroautophagy, alternative autophagy does not require the factors Atg5 and Atg7. Here, the authors show that Wipi3 is essential for alternative autophagy, but not for canonical autophagy, and that Wipi3 functions to maintain neuronal cells via mechanisms different from those of canonical autophagy.
- Hirofumi Yamaguchi
- , Shinya Honda
- & Shigeomi Shimizu
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Article
| Open AccessHsc70/Stub1 promotes the removal of individual oxidatively stressed peroxisomes
Pexophagy removes damaged peroxisomes, which are particularly prone to ROS formation. Here, the authors use light to induce peroxisome turnover by local ROS generation, showing STUB1 translocation is critical and might contribute to human disease.
- Bo-Hua Chen
- , Yao-Jen Chang
- & Wei Yuan Yang
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Article
| Open AccessAutophagy facilitates adaptation of budding yeast to respiratory growth by recycling serine for one-carbon metabolism
Autophagy is important during stress and development, but how the metabolites generated are used by the cell remains unclear. Here, the authors demonstrate that budding yeast require autophagy to provide serine for one-carbon metabolism during the switch from glycolytic to respiratory growth.
- Alexander I. May
- , Mark Prescott
- & Yoshinori Ohsumi
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Article
| Open AccessmTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability
mTORC1 is a key mediator of drug resistance and also regulates autophagy. In this study, the authors demonstrate that cancer cells with acquired drug resistance exibit metabolic vulnerabilities mediated by high levels of mTORC1 and the consequent inhibition of autophagy.
- Niklas Gremke
- , Pierfrancesco Polo
- & Thorsten Stiewe
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Article
| Open AccessLong-term autophagy is sustained by activation of CCTβ3 on lipid droplets
The source of phospholipids to generate autophagosomal membranes, particularly after prolonged starvation, is not well characterized. Here, the authors show that CCTβ3, the rate limiting enzyme in phosphatidylcholine synthesis, is activated on lipid droplets and sustains long-term autophagy.
- Yuta Ogasawara
- , Jinglei Cheng
- & Toyoshi Fujimoto
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Article
| Open AccessAge-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy
Autophagic activity declines with age in several tissues and is linked to aging-associated functional decline and pathologies. Here the authors show that Rubicon, a negative regulator of autophagy, decreases in adipocytes with age, and its loss leads to adipocyte dysfunction via excess autophagic degradation of SRC-1 and TIF2.
- Tadashi Yamamuro
- , Tsuyoshi Kawabata
- & Tamotsu Yoshimori
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Article
| Open AccessAutophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites
How autophagy supports tumor cell metabolism is not fully clear. Here, the authors show that autophagy regulates lipid availability to support mitochondrial oxidative metabolism through mitochondria-endoplasmic reticulum contact sites, necessary for cell proliferation in AML.
- Claudie Bosc
- , Nicolas Broin
- & Carine Joffre
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Article
| Open AccessClearance of HIV infection by selective elimination of host cells capable of producing HIV
The latent human immunodeficiency virus (HIV) reservoir in patients poses a problem for HIV cure. Here, Li et al. show that a combination of compounds inducing viral reactivation and cell death, inhibiting autophagy and blocking new infections can eliminate HIV infection in 50% of humanized HIV infected mice and in blood samples from infected patients.
- Min Li
- , Wei Liu
- & Jin Wang
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Article
| Open AccessRETRACTED ARTICLE: Ornithine-A urea cycle metabolite enhances autophagy and controls Mycobacterium tuberculosis infection
Kupffer cells are more resistant to M. tuberculosis when compared with alveolar macrophages. Here the authors show that this distinction is caused by the presence of ornithine and imidazole in Kupffer cells and that these metabolites can drive autophagy and M. tuberculosis killing in alveolar macrophages when given intranasally to infected mice.
- Ramya Sivangala Thandi
- , Rajesh Kumar Radhakrishnan
- & Ramakrishna Vankayalapati
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Article
| Open AccessSuper-assembly of ER-phagy receptor Atg40 induces local ER remodeling at contacts with forming autophagosomal membranes
The ER is subject to autophagy (ER-phagy) for turnover, with Atg40 acting as a receptor to sequester ER with Atg8 in autophagosomes. Here, the authors show that Atg40 is clustered by interaction with Atg8 to generate local membrane curvature and promote autophagosome packing.
- Keisuke Mochida
- , Akinori Yamasaki
- & Hitoshi Nakatogawa
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Article
| Open AccessProlonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons
Disruption of autophagy function in cellular and animal models of tauopathy increases tau aggregation. Here, the authors describe a small-molecule screen to identify compounds that promote autophagy clearance of tau and rescue disease-relevant phenotypes in tauopathy patient-derived neurons.
- M. Catarina Silva
- , Ghata A. Nandi
- & Stephen J. Haggarty
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Article
| Open AccessLeucine regulates autophagy via acetylation of the mTORC1 component raptor
Leucine is a critical amino acid that inhibits autophagy. Here, the authors show that the leucine inhibits autophagy in most cell types, predominantly via its catabolite acetyl CoA, which drives acetylation of raptor, which activates mTORC1, a negative regulator of this catabolic process.
- Sung Min Son
- , So Jung Park
- & David C. Rubinsztein
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Article
| Open AccessTECPR1 promotes aggrephagy by direct recruitment of LC3C autophagosomes to lysosomes
Many neurodegenerative disorders are characterised by the accumulation of protein aggregates in neurons. Here, the authors show that the lysosomal protein TECPR1 selectively recruits mature autophagosomes via an interaction with LC3C to break down protein aggregates in neural stem cells.
- Lisa Wetzel
- , Stéphane Blanchard
- & Thomas Wollert
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Article
| Open AccessAutophagy controls the induction and developmental decline of NMDAR-LTD through endocytic recycling
NMDA receptor-dependent long-term depression (NMDAR-LTD) is a form of synaptic plasticity mediated by reduced recycling of AMPA receptors to the plasma membrane. Here the authors show that autophagy is a regulator of this endocytic recycling and autophagy upregulation dampens NMDAR-LTD in adulthood.
- Hongmei Shen
- , Huiwen Zhu
- & Zheng Li