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| Open AccessAutophagy differentially regulates TNF receptor Fn14 by distinct mammalian Atg8 proteins
The TNF receptor Fn14 is a short-lived protein. Here the authors show that Fn14 turnover is regulated by selective autophagy, with different ATG8 proteins having distinct roles during the process.
- Hila Winer
- , Milana Fraiberg
- & Zvulun Elazar
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Article
| Open AccessCoordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD
Niemann-Pick type C1 disease is most commonly caused by the allele NPC1 I1061T, which is misfolded in the ER and rapidly degraded by the ubiquitin proteasome system. Here the authors show that the I1061T mutant is also degraded by ER-phagy.
- Mark L. Schultz
- , Kelsey L. Krus
- & Andrew P. Lieberman
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Article
| Open AccessPhosphorylation of ULK1 affects autophagosome fusion and links chaperone-mediated autophagy to macroautophagy
The ULK complex plays a well-known role in initiating autophagy, to recycle cellular components in response to nutritional stress. Here, the authors demonstrate a late role for ULK in auotophagosome–lysosome fusion and provide a direct link between macroautophagy and chaperone mediated autophagy.
- Chenyao Wang
- , Huafei Wang
- & Zhixue Liu
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Article
| Open AccessmTOR-dependent phosphorylation controls TFEB nuclear export
On amino acid deprivation TFEB translocates from the cytoplasm to the nucleus. Here the authors identify a nuclear export signal in TFEB that is recognized by the exportin CRM1, and show that dual phosphorylation at S142 and S138 by mTOR accelerates export of TFEB.
- Gennaro Napolitano
- , Alessandra Esposito
- & Andrea Ballabio
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Article
| Open AccessInsights into degradation mechanism of N-end rule substrates by p62/SQSTM1 autophagy adapter
The autophagy adapter p62/SQSTM1 plays a key role in selective autophagy and also recognizes N-end rule substrates. Here the authors provide molecular insights into p62 N-end rule substrate recognition by solving the structures of the p62 ZZ-domain in complex with various type 1 and type 2 degrons and also show the pH dependent oligomerization of p62.
- Do Hoon Kwon
- , Ok Hyun Park
- & Hyun Kyu Song
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Article
| Open AccessContact inhibition controls cell survival and proliferation via YAP/TAZ-autophagy axis
At high cell density or when plated on soft matrix, YAP/TAZ are redistributed from the nucleus to the cytosol, becoming transcriptionally inactive. Here the authors show that at high cell density, autophagosome formation is impaired due to reduced YAP/TAZ-dependent transcription of actomyosin genes
- Mariana Pavel
- , Maurizio Renna
- & David C. Rubinsztein
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Article
| Open AccessAn autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure
During autophagy, phagophores elongate to form double-membrane vesicles but the mechanism behind their closure is unknown. Here, the authors develop an autophagy assay and find a role for the endosomal sorting complexes required for transport component CHMP2A as a phagophore closure regulator.
- Yoshinori Takahashi
- , Haiyan He
- & Hong-Gang Wang
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Article
| Open AccessA complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy
Many Amyotrophic Lateral Sclerosis (ALS)-linked mutations cause accumulation of stress granules, and most ALS cases are caused by repeat expansions in C9ORF72. Here the authors show that C9ORF72 and the autophagy receptor p62 interact to associate with proteins symmetrically dimethylated on arginines such as FUS, to eliminate stress granules by autophagy.
- Maneka Chitiprolu
- , Chantal Jagow
- & Derrick Gibbings
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Article
| Open AccessTBK-binding protein 1 regulates IL-15-induced autophagy and NKT cell survival
Interleukin-15 (IL-15) regulates the homeostasis of many immune cell types, including natural killer T (NKT) cells, but the underlying mechanism is not completely clear. Here the authors analyse Tbkbp1-deficient mice and show that IL-15 induces Tbkbp1-dependent autophagy to modulate NKT survival.
- Lele Zhu
- , Xiaoping Xie
- & Shao-Cong Sun
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Article
| Open AccessAutophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence
Highly metastatic dormant cancer cells contribute to breast cancer recurrence, but the underlying mechanism is less understood. Here, the authors show that dormant breast cancer cells depend on autophagy to ensure their long term survival and distant recurrence
- Laura Vera-Ramirez
- , Suman K. Vodnala
- & Jeffrey E. Green
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Article
| Open AccessNon-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy
DAPK2 is a calmodulin-regulated protein kinase implicated in autophagy regulation, but how physiological stress leads to its activation is yet unknown. Here, the authors show that the central metabolic sensor AMPK phosphorylates DAPK2 to promote autophagy in a calmodulin-independent mechanism.
- Ruth Shiloh
- , Yuval Gilad
- & Adi Kimchi
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Article
| Open AccessA novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes
Autophagy plays an important role in metabolic functions and increased autophagic activity may be beneficial for metabolic disorders. Here the authors screen a chemical library for enhancer of autophagic flux and identify small molecules that improve the metabolic profile by increasing lysosomial functions.
- Hyejin Lim
- , Yu-Mi Lim
- & Myung-Shik Lee
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Article
| Open AccessBeclin1 restricts RNA virus infection in plants through suppression and degradation of the viral polymerase
Plant DNA virus replication is inhibited by autophagy, but the interplay between plant RNA viruses and autophagy is less clear. Here, Li et al. show that turnip mosaic virus infection activates autophagy and that Beclin1, a core autophagy component, binds the viral polymerase and inhibits virus replication.
- Fangfang Li
- , Changwei Zhang
- & Aiming Wang
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Article
| Open AccessMAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB
Amino acids stimulate cell growth and depletion in a cell activates autophagy, yet how this is regulated is unclear. Here, the authors show that MAP4K3 (also known as germinal-center kinase-like kinase) acts as an amino acid-dependent regulator of autophagy, via phosphorylation of the transcription factor EB.
- Cynthia L. Hsu
- , Elian X. Lee
- & Albert R. La Spada
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Article
| Open AccessThe IAP family member BRUCE regulates autophagosome–lysosome fusion
The inhibitor of apoptosis (IAP) protein, BRUCE is known to ubiquitinate apoptosis regulators for proteasomal degradation. Here the authors show that BRUCE provides a bridge between LAMP2 on lysosomes and Atg8 family proteins on autophagosomes to support autophagosome-lysosome fusion.
- Petra Ebner
- , Isabella Poetsch
- & Fumiyo Ikeda
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Article
| Open AccessOxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis
The cellular mechanisms underlying autophagy are conserved; however it is unclear how they evolved in higher organisms. Here the authors identify two oxidation-sensitive cysteine residues in the autophagy receptor SQSTM1/p62 in vertebrates which allow activation of pro-survival autophagy in stress conditions.
- Bernadette Carroll
- , Elsje G. Otten
- & Viktor I. Korolchuk
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Article
| Open AccessImpaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney
Nephropathic cystinosis is a lysosomal storage disease characterized by proximal tubular cell dysfunction. Here Festa and colleagues show that these lysosomal alterations lead to defective autophagic clearance of mitochondria and increased oxidative stress that, in turn, activates the transcription factor ZONAB leading to impaired cell differentiation.
- Beatrice Paola Festa
- , Zhiyong Chen
- & Alessandro Luciani
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Article
| Open AccessOxidation of Atg3 and Atg7 mediates inhibition of autophagy
A dysfunction of autophagy can be detected in aged tissues, but how this is regulated is unclear. Here, the authors show in vitro and in aged mice aorta, that inhibition of LC3 lipidation under conditions of oxidative stress causes oxidation of Atg3 and Atg7, preventing autophagosome maturation.
- Karen Frudd
- , Thomas Burgoyne
- & Joseph Robert Burgoyne
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Article
| Open AccessLncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription
Little is known about the role of long lncRNAs in autophagy. The authors identify lncCAIF, and show that it suppresses cardiac autophagy and attenuates myocardial infarction by targeting p53 -mediated transcription of myocardin.
- Cui-Yun Liu
- , Yu-Hui Zhang
- & Kun Wang
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| Open AccessSmall-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan
Activation of autophagy, via the transcription factor TFEB, is a promising strategy to treat metabolic diseases. Here, the authors report three novel classes of small molecules that promote TFEB nuclear translocation, and provide evidence for the therapeutic efficacy of these compounds in mice and worms.
- Chensu Wang
- , Hanspeter Niederstrasser
- & Michael A. White
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Article
| Open AccessANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ
NF-κB activation mediated by TNFα has a critical role in inflammation; however, the underlying mechanisms await further investigation. Here the authors show that selective autophagy regulates NF-κB activation via an ANGPTL8/p62-IKKγ signaling axis.
- Yu Zhang
- , Xian Guo
- & Kun Huang
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Article
| Open AccessDendrogenin A drives LXR to trigger lethal autophagy in cancers
Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.
- Gregory Segala
- , Marion David
- & Sandrine Silvente-Poirot
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Article
| Open AccessPhosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy
The endoplasmic reticulum (ER) and lysosome are central to cellular stress responses, but it is unclear how ER stress is signaled to lysosomes. Here the authors show that ER stress activates chaperone-mediated autophagy (CMA) via direct phosphorylation of the CMA receptor LAMP2A by the lysosomal p38 MAPK.
- Wenming Li
- , Jinqiu Zhu
- & Zixu Mao
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Article
| Open AccessAutophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins
Macroautophagy can regulate cell signalling and tumorigenesis but the molecular mechanisms are unclear. Here the authors show selective degradation of the signalling scaffold TRAF3 by autophagy and consequent activation of the NF-κB family member RELB regulate gene expression via antagonism of SMAD proteins.
- Alice C. Newman
- , Alain J. Kemp
- & Simon Wilkinson
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Article
| Open AccessKenny mediates selective autophagic degradation of the IKK complex to control innate immune responses
Selective autophagy describes the selective degradation of cellular components upon stress or nutrient deficiency, but whether it modulates innate immunity is unclear. Here the authors show that Drosophila Kenny may be an evolution-selected autophagy receptor for the down-regulation of innate NF-κB activation
- Radu Tusco
- , Anne-Claire Jacomin
- & Ioannis P. Nezis
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Article
| Open AccessPlekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
Accumulating evidence suggests that disruption of autophagy is associated with neurodegeneration. Here the authors show that Plekhg5 acts as a GEF for Rab26, a small GTPase that promotes the autophagy of synaptic vesicles in neurons; mice lacking Plekgh5 develop late-onset motoneuron degeneration.
- Patrick Lüningschrör
- , Beyenech Binotti
- & Michael Sendtner
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Article
| Open AccessCaMKII-mediated Beclin 1 phosphorylation regulates autophagy that promotes degradation of Id and neuroblastoma cell differentiation
Neuroblastoma cell differentiation is regulated by Id proteins. Here, the authors show that CaMKII-mediated phosphorylation of Beclin 1 can activate K63-linked ubiquitination and autophagic degradation of Id proteins uncovering a role for autophagy in cell differentiation.
- Xuan Li
- , Xiao-Qi Wu
- & Xiao-Feng Zhu
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Article
| Open AccessA conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction
KLF family transcription factors (KLFs) regulate many cellular processes, including proliferation, survival and stress responses. Here, the authors position KLFs as important regulators of autophagy and lifespan in C. elegans, a role that may extend to the modulation of age-associated vascular phenotypes in mammals.
- Paishiun N. Hsieh
- , Guangjin Zhou
- & Mukesh K. Jain
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Article
| Open AccessCross-talk between miR-471-5p and autophagy component proteins regulates LC3-associated phagocytosis (LAP) of apoptotic germ cells
Although phagocytic clearance of apoptotic germ cells by Sertoli cells is essential for spermatogenesis, little of the mechanism is known. Here the authors show that Sertoli cells employ LC3-associated phagocytosis (LAP) by recruiting autophagy member proteins to clear apoptotic germ cells.
- Subbarayalu Panneerdoss
- , Suryavathi Viswanadhapalli
- & Manjeet K. Rao
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Article
| Open AccessThe autophagy initiator ULK1 sensitizes AMPK to allosteric drugs
AMPK is involved in sensing of metabolic stress. The authors show that the autophagy initiator ULK1 phosphorylates β1-Ser108 on the regulatory β1-subunit, sensitizing AMPK to allosteric drugs, and activates signaling pathways that appear independent of Thr172 phosphorylation in the kinase activation loop.
- Toby A. Dite
- , Naomi X. Y. Ling
- & Jonathan S. Oakhill
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Article
| Open AccessAmpk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy
Exercise is associated with biogenesis and removal of dysfunctional mitochondria. Here the authors use a mitochondrial reporter gene to demonstrate the occurrence of mitophagy following exercise in mice, and show this is dependent on AMPK and ULK1 signaling.
- Rhianna C. Laker
- , Joshua C. Drake
- & Zhen Yan
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Article
| Open AccessSelective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of TH9 cells
Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate TH9 homeostasis and antitumour immunity.
- Thaiz Rivera Vargas
- , Zhijian Cai
- & Lionel Apetoh
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Article
| Open AccessGlutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation
mTORC1 is a critical kinase that regulates cell growth and proliferation. Here the authors show that glutamine metabolism is sufficient to restore mTORC1 activity during prolonged amino acid starvation in an autophagy-dependent manner.
- Hayden Weng Siong Tan
- , Arthur Yi Loong Sim
- & Yun Chau Long
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Article
| Open AccessAtg4 proteolytic activity can be inhibited by Atg1 phosphorylation
The protease Atg4 mediates Atg8 lipidation, required for autophagosome biogenesis, but also triggers Atg8 release from the membranes, however is unclear how these steps are coordinated. Here the authors show that phosphorylation by Atg1 inhibits Atg4 at autophagosome formation sites.
- Jana Sánchez-Wandelmer
- , Franziska Kriegenburg
- & Fulvio Reggiori
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Article
| Open AccessA reversible phospho-switch mediated by ULK1 regulates the activity of autophagy protease ATG4B
Upon autophagy induction, LC3 is cleaved by the protease ATG4 and conjugated to the autophagosomal membrane; however, its removal is mediated by the same protease. Here the authors show that ULK1-mediated phosphorylation and PP2A-mediated dephosphorylation of ATG4 regulates its cellular activity to control LC3 processing.
- N. Pengo
- , A. Agrotis
- & R. Ketteler
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Article
| Open Accessp62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis
Soluble misfolded proteins that fail to be degraded by the ubiquitin proteasome system (UPS) are redirected to autophagy via specific adaptors, such as p62. Here the authors show that p62 recognises N-degrons in these proteins, acting as a N-recognin from the proteolytic N-end rule pathway, and targets these cargos to autophagosomal degradation.
- Hyunjoo Cha-Molstad
- , Ji Eun Yu
- & Bo Yeon Kim
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Article
| Open AccessHypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation
Hypoxia and HIF-1α activation are protective in mouse models of colitis, and the latter regulates autophagy. Here Cosin-Roger et al. show that hypoxia ameliorates intestinal inflammation in Crohn’s patients and murine colitis models by inhibiting mTOR/NLRP3 pathway and promoting autophagy.
- Jesus Cosin-Roger
- , Simona Simmen
- & Pedro A. Ruiz
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Article
| Open AccessCDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers
CDK4/6-Cyclin D pathway is often deregulated in cancer; therefore specific inhibitors have been developed. Here the authors show that treatment with CDK4/6 inhibitors activate autophagy in breast cancer cells; thus, combination of such inhibitors with autophagy inhibitors results in a synergistic effect on tumour growth.
- Smruthi Vijayaraghavan
- , Cansu Karakas
- & Khandan Keyomarsi
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Article
| Open AccessMultiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling
MAVS is an essential component of the pathogen-sensing machinery, and functions by forming prion-like filaments. Here the authors show that alternatively translated forms of truncated endogenous MAVS can prevent spontaneous aggregation and degradation in cells to sustain MAVS-mediated immune signalling.
- Nan Qi
- , Yuheng Shi
- & Fajian Hou
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Article
| Open AccessExploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis
Dysfunction of autophagy in plaque macrophages aggravates atherosclerosis. Here the authors show that induction of macrophage autophagy–lysosomal biogenesis either genetically by overexpression of the master transcriptional regulator of this process, TFEB, or pharmacologically with trehalose is atheroprotective.
- Ismail Sergin
- , Trent D. Evans
- & Babak Razani
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Article
| Open AccessWIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy
During autophagy, AMPK and mTOR associate with ULK1 and regulate phosphatidylinositol 3-phosphate (PtdIns3P) production that mediates autophagosome formation via WIPI proteins. Here the authors show WIPI3 and WIPI4 have a scaffolding function upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes.
- Daniela Bakula
- , Amelie J. Müller
- & Tassula Proikas-Cezanne
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Article
| Open AccessLegionella effector Lpg1137 shuts down ER-mitochondria communication through cleavage of syntaxin 17
The pathogenic bacteriumLegionella pneumophila replicates within macrophages. Here, the authors show that L. pneumophilasecretes an effector protein that cleaves the host protein syntaxin 17, thus inhibiting autophagy and staurosporine-induced apoptosis in the host cell.
- Kohei Arasaki
- , Yumi Mikami
- & Mitsuo Tagaya
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Article
| Open AccessRetrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration
The endocytic adaptor protein complex AP-2 is mostly known for its role in endocytosis and in synaptic vesicle reformation. Here the authors show that AP-2 also mediates retrograde transport of TrkB-containing autophagosomes in neurons; this process promotes neuronal complexity and prevents the degeneration of cortical and thalamic neurons.
- Natalia L. Kononenko
- , Gala A. Claßen
- & Volker Haucke
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Article
| Open AccessA semisynthetic Atg3 reveals that acetylation promotes Atg3 membrane binding and Atg8 lipidation
Acetylation of Atg3 regulates lipidation of Atg8 and therefore autophagy, but the molecular mechanisms remain unclear. Here, Liet al. semi-synthesize diacetylated Atg3, allowing them to show that acetylated Atg3 enhances Atg8 lipidation by promoting interaction of Atg3 with liposomes containing physiological levels of phosphatidylethanolamine.
- Yi-Tong Li
- , Cong Yi
- & Lei Liu
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Article
| Open AccessStructure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation
Parkin and PINK1 are involved in damaged mitochondria clearance; however the sequence of events of Parkin activation is not clear. Here, the authors show that binding to phospho-ubiquitin on mitochondria enables Parkin phosphorylation, which allows Repressor Element of Parkin removal, E3 ligase activation and mitophagy.
- Matthew Y. Tang
- , Marta Vranas
- & Edward A. Fon
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Article
| Open AccessHaploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer
Cancers accumulate multiple single copy number alterations, but their impact is unclear. Here, the authors computationally demonstrate a disruption of genes associated with autophagy in ovarian cancer, show impact on autophagic flux, and note the efficacy of autophagy drugs in preclinical models.
- Joe Ryan Delaney
- , Chandni B. Patel
- & Dwayne G. Stupack
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Article
| Open AccessHormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans
Mild heat stress has beneficial effects on organismal health and survival. Here, Kumstaet al. show that a mild heat shock and HSF-1 overexpression induce autophagy in multiple tissues of C. elegansand autophagy-related genes are essential for both heat shock-induced and HSF-1–mediated stress resistance and longevity.
- Caroline Kumsta
- , Jessica T. Chang
- & Malene Hansen
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Article
| Open AccessA Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance
Damaged mitochondria are normally cleared through canonical and alternative autophagy pathways. Here, the authors report that mitochondria can be cleared through an autophagy-independent endosomal-lysosomal pathway that depends on Parkin-dependent sequestration of mitochondria in Rab5-positive early endosomes.
- Babette C. Hammerling
- , Rita H. Najor
- & Åsa B. Gustafsson
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Article
| Open AccessmTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation
Inhibitors of the mTORC1 pathway are considered anti-cancer drugs. Here, the authors show that on nutrient restriction, glutaminolysis-induced activation of mTORC1 induces apoptosis via inhibiting autophagy, highlighting that under such conditions inhibition of mTORC1 results in survival of cancer cells.
- Victor H. Villar
- , Tra Ly Nguyen
- & Raúl V. Durán