Featured
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| Open AccessTRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation
cGAS/STING activation is linked to the induction of anti-tumor immune responses. Here the authors report a role for the deubiquitinating enzyme TRABID in regulating mitotic cell division and suppressing anti-tumor immunity, suggesting that TRABID inhibition induces micronuclei and activates cGAS/STING pathway.
- Yu-Hsuan Chen
- , Han-Hsiun Chen
- & Ruey-Hwa Chen
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Article
| Open AccessRedefining the role of AMPK in autophagy and the energy stress response
According to the current understanding in the field, AMPK promotes autophagy by activating ULK1 during energy stress. Here, authors show that AMPK is indeed a negative regulator of ULK1 and it suppresses autophagy in energy depleted cells.
- Ji-Man Park
- , Da-Hye Lee
- & Do-Hyung Kim
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Article
| Open AccessPhospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism
Phospholipase D3 polymorphisms are linked to late-onset Alzheimer’s disease but the mechanisms are not understood. Van Acker and colleagues show that Phospholipase D3 processes mitochondrial DNA in lysosomes to maintain lysosomal homeostasis and proper degradation of the amyloid precursor protein.
- Zoë P. Van Acker
- , Anika Perdok
- & Wim Annaert
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Article
| Open AccessGenetically prolonged beige fat in male mice confers long-lasting metabolic health
Beige adipocytes quickly transition into white adipocytes upon the removal of stimuli, limiting their therapeutic potential for chronic metabolic diseases. In this study, the authors show that inhibiting Cdkn2a-Becn1 mediated autophagy can maintain beige adipocytes and provide long term metabolic health benefits in mice.
- Ruifan Wu
- , Jooman Park
- & Yuwei Jiang
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Article
| Open AccessNext-generation large-scale binary protein interaction network for Drosophila melanogaster
Maps of protein-protein interactions (PPIs) help identify new components of pathways, complexes, and processes. In this work, state-of-the-art methods are used to identify binary Drosophila PPIs, generating broadly useful physical and data resources.
- Hong-Wen Tang
- , Kerstin Spirohn
- & Stephanie E. Mohr
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Article
| Open AccessDe novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics
The function of de novo lipogenesis (DNL) in adipocytes has been a mystery as it contributes little to fat storage in these cells. Here, the authors show that DNL is a critical source of fatty acids for membrane-expanding processes like autophagy.
- Leslie A. Rowland
- , Adilson Guilherme
- & Michael P. Czech
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Article
| Open AccessMYTHO is a novel regulator of skeletal muscle autophagy and integrity
Here, the authors identify a novel regulator of autophagy, skeletal muscle mass and integrity named MYTHO. Silencing MYTHO protects against muscle atrophy in a wide range of acute catabolic conditions, while prolonged silencing causes a severe myopathy.
- Jean-Philippe Leduc-Gaudet
- , Anais Franco-Romero
- & Gilles Gouspillou
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Article
| Open AccessAutophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling
Lymphatic malformation (LM) is a rare, non-malignant vascular abnormality that can progress to lymphangiosarcoma (LAS). The authors use genetic mouse models to show that autophagy inhibition blocks the progression of LM to LAS by decreasing osteopontin expression and Jak/Stat signalling.
- Fuchun Yang
- , Shiva Kalantari
- & Jun-Lin Guan
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Article
| Open AccessThe metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans
Understanding how metabolites modulate longevity is crucial for reducing aging-related disease. Here, the authors demonstrate that α-ketobutyrate exhibits an anti-aging effect by coordinating NAD + -SIRT1 signaling and peroxisome function.
- Nan Wu
- , Yi-Cheng Ma
- & Cheng-Gang Zou
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Article
| Open AccessModulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open AccessThe UFM1 system regulates ER-phagy through the ufmylation of CYB5R3
The UFM1 system, a ubiquitin-like conjugation system is crucial for endoplasmic reticulum (ER) homeostasis. Here, authors found that CYB5R3 is covalently conjugated with UFM1, which becomes a signal for ER-phagy, a selective autophagy of ER.
- Ryosuke Ishimura
- , Afnan H. El-Gowily
- & Masaaki Komatsu
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Article
| Open AccessUSP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity
Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.
- Juan Li
- , Yang Wang
- & Zhi-Xiong Jim Xiao
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Article
| Open AccessSESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing
How H3T11 phosphorylation exerts biological functions remains poorly understood. Here, authors show that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing.
- Fei He
- , Qi Yu
- & Shanshan Li
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Article
| Open AccessPexophagy suppresses ROS-induced damage in leaf cells under high-intensity light
Pexophagy plays a pivotal role in the selective removal of ROS-generating peroxisomes, which protects plants from oxidative damage during photosynthesis under high-intensity light.
- Kazusato Oikawa
- , Shino Goto-Yamada
- & Mikio Nishimura
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Article
| Open AccessYAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro
Growing evidence indicates that YAP/TAZ transcriptional regulators promote autophagy. Here, the authors characterize the role of YAP against Staphyloccocus aureus infection of synovial organoids and describe the role staphylococcal toxins have in antagonizing YAP-mediated functions.
- Robin Caire
- , Estelle Audoux
- & Paul O. Verhoeven
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Article
| Open AccessMitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA
Mitochondrial quality control mechanisms prevent damage accumulation, including in mitochondrial DNA (mtDNA). Here, Sen et al. show that altered mtDNA elicits local rearrangements in mitochondrial membrane potential and cristae structure, with mtDNA eliminated through VPS35 endosomes.
- Ayesha Sen
- , Sebastian Kallabis
- & David Pla-Martín
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Article
| Open AccessSpatially resolved phosphoproteomics reveals fibroblast growth factor receptor recycling-driven regulation of autophagy and survival
Recruitment of Receptor Tyrosine Kinase signalling partners during endocytosis, specifically during recycling to the plasma membrane, is crucial to signal propagation and regulation. Here, the authors reveal FGFR signalling partners proximal to recycling endosomes with a spatially resolved phosphoproteomics approach.
- Joanne Watson
- , Harriet R. Ferguson
- & Chiara Francavilla
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Article
| Open AccessMulti-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy
Autophagy has been typically associated with resistance to cancer therapy, and autophagy inhibitors have been explored in cancer. Here, the authors investigate autophagy signatures and their association with drug response in cancer, and find that autophagy induction can actually sensitise cancer cells to therapy.
- Mei Luo
- , Lin Ye
- & Leng Han
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Article
| Open AccessThe cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics
The functions of specific lipids in autophagosome biogenesis are not entirely clear. Here, the authors show that the ER protein GRAMD1C, a cholesterol transport protein, suppresses autophagy initiation and has roles in mitochondrial cholesterol homeostasis and respiration.
- Matthew Yoke Wui Ng
- , Chara Charsou
- & Anne Simonsen
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Article
| Open AccessInduction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D
Alcohol consumption promotes neutral fat accumulation in the liver. Here, the authors report that alcohol induces aryl hydrocarbon receptor AhR in the liver, and hepatocyte-specific AhR deletion protects against alcohol induced accumulation potentially via transcriptional regulation of Protein phosphatase 2 regulatory subunit Bdelta and subsequent effects on autophagy.
- Yun Seok Kim
- , Bongsub Ko
- & Sang Geon Kim
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Article
| Open AccessRNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy
Little is known about how proteostasis is maintained during viral infection. Here, the authors identify unexpected crosstalk between the calnexin cycle, ERAD, and reticulophagy, resulting in suppression of ebolavirus glycoprotein expression.
- Jing Zhang
- , Bin Wang
- & Yong-Hui Zheng
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Article
| Open AccessAutophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA
The role of eiptranscriptomic modifications in autophagy is unclear. Here, the authors show that the m6A reader YTHDF3 functions as a nutrient responder to recognize upregulated m6A modification, promoting FOXO3 translation to subsequently initiate autophagy.
- WeiChao Hao
- , MeiJuan Dian
- & Dong Xiao
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Article
| Open AccessPhosphorylation of Jhd2 by the Ras-cAMP-PKA(Tpk2) pathway regulates histone modifications and autophagy
How cells transduce nutrient availability to appropriate gene expression remains poorly understood. Here the authors show that the nutrient sensor, protein kinase A modulates histone modifications and gene transcription by phosphorylating histone demethylase.
- Qi Yu
- , Xuanyunjing Gong
- & Shanshan Li
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Article
| Open AccessTraB family proteins are components of ER-mitochondrial contact sites and regulate ER-mitochondrial interactions and mitophagy
Contact sites permit the exchange of signals and materials between organelles. Here the authors characterize a protein complex associated with an ER-mitochondrial contact site in Arabidopsis that is required for mitochondrial function and mitochondrial turnover
- Chengyang Li
- , Patrick Duckney
- & Pengwei Wang
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Article
| Open AccessSuppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy
SARS- CoV-2 hijacks ACE2 for cell entry. Here, the authors report that dynamic SUMOylation modulates the TOLLIP-directed selective autophagic degradation of ACE2 and suggest SUMOylation inhibition as a potential intervention against SARS-CoV-2 infection.
- Shouheng Jin
- , Xing He
- & Jun Cui
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Article
| Open AccessProtein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy
Mitophagy activation is mediated by mitochondrial depolarization. Here, the authors show that mitochondrial protein misfolding can activate mitophagy in a depolarization-independent manner mediated by a protein import reduction.
- Jonas Benjamin Michaelis
- , Melinda Elaine Brunstein
- & Christian Münch
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Article
| Open AccessPhosphatidylinositol-4-phosphate controls autophagosome formation in Arabidopsis thaliana
Autophagosomes are specialized vesicles that target and deliver cargo to the lytic vacuole. Here the authors show that plasma-membrane derived lipid phosphatidylinositol-4-phosphate supports the assembly and expansion of autophagosomes in Arabidopsis
- Rodrigo Enrique Gomez
- , Clément Chambaud
- & Amélie Bernard
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Article
| Open AccessTargeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
Gomez-Sintes et al. have developed small molecules that selectively activate chaperone-mediated autophagy by stabilizing the interaction between retinoic acid receptor alpha and its co-repressor N-CoR1. They demonstrate the protective effect of boosting chaperone-mediated autophagy against retinal degeneration.
- Raquel Gomez-Sintes
- , Qisheng Xin
- & Ana Maria Cuervo
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Article
| Open AccessCompounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance
Several neurodegenerative diseases are characterized by the aggregation of cytoplasmic proteins. Here, the authors demonstrate that the small molecule SMER28 activates VCP, which enhances both autophagic and proteasomal clearance of aggregate-prone proteins.
- Lidia Wrobel
- , Sandra M. Hill
- & David C. Rubinsztein
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Article
| Open AccessEndosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation
Autophagy can selectively target cargo for degradation. Here the authors map the proximal interactome of ATG8-paralogs LC3B and LC3C uncovering an LC3C-Endocytic-Associated-Pathway that selectively recruits internalized plasma membrane cargo, Met and transferrin receptors, to nascent autophagosomes.
- Paula P. Coelho
- , Geoffrey G. Hesketh
- & Morag Park
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Article
| Open AccessA degradative to secretory autophagy switch mediates mitochondria clearance in the absence of the mATG8-conjugation machinery
The mechanisms underlying mitochondrial quality control are not fully understood. Here the authors identify a switch from degradative to secretory autophagy in the absence of the mATG8-conjugation system, termed Autophagic Secretion of Mitochondria.
- Hayden Weng Siong Tan
- , Guang Lu
- & Han-Ming Shen
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Article
| Open AccessStructural mechanism of protein recognition by the FW domain of autophagy receptor Nbr1
Nbr1 recognizes cargos in selective autophagy. Here, authors show filamentous yeast Nbr1 binds Ams1 via an FW domain, and the cryo-EM structure reveals that Nbr1 recognizes the N-terminal di-glycine and tetrameric assembly of Ams1.
- Jianxiu Zhang
- , Ying-Ying Wang
- & Keqiong Ye
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Article
| Open AccessMacrophages disseminate pathogen associated molecular patterns through the direct extracellular release of the soluble content of their phagolysosomes
The detection of conserved motifs by pattern recognition receptors is a crucial component of the innate detection of pathogens and danger signals via conserved pattern recognition receptors. Here the authors define a pathway that transfers partially digested material from the phagolysosomal pathway of macrophages to release at the plasma membrane which is associated with enhanced inflammatory potential, by a process they introduce as eructophagy.
- Catherine J. Greene
- , Jenny A. Nguyen
- & Robin M. Yates
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Perspective
| Open AccessAutophagy regulation by RNA alternative splicing and implications in human diseases
Both alternative splicing and autophagy are core cell biological processes, but where they intersect has received little attention. Here, the authors reflect on recent connections identified between these pathways and consider their impact on human disease.
- Patricia González-Rodríguez
- , Daniel J. Klionsky
- & Bertrand Joseph
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Article
| Open AccessPantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism
PKAN and PD are two distinct diseases with overlapping pathophysiology. Here, authors show that their pathogenic genes PANK2 and PINK1 interact. PANK2 regulates mitophagy via CoA metabolism, while PINK1 supervises PANK2 translation on mitochondria.
- Yunpeng Huang
- , Zhihui Wan
- & Bing Zhou
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Article
| Open AccessLC3B is an RNA-binding protein to trigger rapid mRNA degradation during autophagy
LC3/ATG8 plays an essential role in autophagy. Here the authors show that LC3B exhibits RNA-binding ability and induces rapid degradation of target mRNAs via autophagic activation, highlighting the interplay between autophagy and RNA biology.
- Hyun Jung Hwang
- , Hongseok Ha
- & Yoon Ki Kim
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Article
| Open AccessAutophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23
The function of autophagy and how this affects non-alcoholic fatty liver disease is not fully known. Here the authors show that in mice with a targeted disruption of the autophagy pathway in CD11c+ cells, development of NAFLD is accelerated involving IL-23 and blocking of IL-23 reduces disease.
- Lauriane Galle-Treger
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessLysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress
Autophagy is important for pancreatic β-cell function, however, the role of mitophagy and mechanism for mitophagy in β-cells are unclear. Here the authors report that in stressed β-cells, lysosomal Ca2+ release promotes mitophagy via activation of the transcription factor EB (TFEB) and loss of β-cell TFEB aggravates glucose intolerance during high-fat diet.
- Kihyoun Park
- , Hyejin Lim
- & Myung-Shik Lee
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Article
| Open AccessOxygen-sensitive methylation of ULK1 is required for hypoxia-induced autophagy
Hypoxia induces mitochondrial clearance and autophagy, although the upstream mechanisms are not well defined. Here, the authors identify that oxygen-sensitive methylation of the key autophagy regulator ULK1 promotes ULK1 activation and subsequent autophagosome formation and mitochondrial clearance.
- Jingyi Li
- , Tao Zhang
- & Rui Liu
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Article
| Open AccessKansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice
Here the authors show that the Koolen-de Vries syndrome associated gene KANSL1 modulates autophagosome-lysosome fusion via transcriptional regulation of autophagosomal gene Syntaxin17, and that 13-cis retinoic acid can reverses mitophagic defects and neurobehavioural abnormalities of mice lacking Kansl1.
- Ting Li
- , Dingyi Lu
- & Xin Pan
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Article
| Open AccessThe AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
Targeted protein degradation is a promising approach for basic research and therapeutic applications. Here, the authors develop a targeted protein degradation platform called AUTOTAC to degrade oncoproteins and neurodegeneration-associated proteins via the p62-dependent autophagy-lysosome system.
- Chang Hoon Ji
- , Hee Yeon Kim
- & Yong Tae Kwon
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Article
| Open AccessDendritic autophagy degrades postsynaptic proteins and is required for long-term synaptic depression in mice
Pruning dendritic spines requires autophagy. Here, the authors show that autophagy is required for long-term depression (LTD), a major form of synaptic plasticity. LTD induces the biogenesis of autophagic vesicles locally in dendrites to facilitate the degradation of postsynaptic proteins.
- Emmanouela Kallergi
- , Akrivi-Dimitra Daskalaki
- & Vassiliki Nikoletopoulou
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Article
| Open AccessGalectin-9 restricts hepatitis B virus replication via p62/SQSTM1-mediated selective autophagy of viral core proteins
In human cells, invading pathogens trigger an innate immune response that helps prevent viral replication and spread. Here, the authors reveal a mechanism of innate immunity that selectively leads to the autophagic degradation of hepatitis B virus core protein.
- Kei Miyakawa
- , Mayuko Nishi
- & Akihide Ryo
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Article
| Open AccessSpatial control of avidity regulates initiation and progression of selective autophagy
The molecular principles governing the initiation of autophagosome formation are not clearly understood. Here we show that the vacuolar protein Vac8 coordinates this process by promoting an avidity-driven assembly of several autophagy factors.
- David M. Hollenstein
- , Mariya Licheva
- & Claudine Kraft
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Article
| Open AccessAcetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming
Lactic acidosis is a metabolic state that occurs in injured tissues. Here the authors show that macrophages, in order to remain functional in acidosis, reduce their mitochondrial mass by mitophagy and rely on autophagy for survival, with mitochondrial integrity retained using acetoacetate as alternative fuel.
- Clément Adam
- , Léa Paolini
- & Pascale Jeannin
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Article
| Open AccessThe autophagy protein ATG9A enables lipid mobilization from lipid droplets
ATG9A is transmembrane autophagic machinery protein that delivers phospholipids to expanding autophagosomes. Mailler et al. show that ATG9A is required to mobilize lipids from lipid droplets for autophagosome expansion as well as mitochondrial fatty acid import and β-oxidation.
- Elodie Mailler
- , Carlos M. Guardia
- & Juan S. Bonifacino
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Article
| Open AccessThe APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages
Inflammasome regulation is not fully understood. Here the authors show that the early endosomal APPL1-Rab5 axis removes damaged mitochondria and then restricts the inflammasome response in macrophages, alleviating the inflammatory diseases.
- Kelvin Ka Lok Wu
- , KeKao Long
- & Kenneth King Yip Cheng
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Article
| Open AccessmTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation
Autophagy relies on coordinated fusion of organelle membranes, although the interplay between the regulatory machinery is not well studied. Here, the authors show that SNARE complex formation is inhibited by mTORC1 phosphorylation of VAMP8, which prevents autophagosome-lysosome fusion.
- Hong Huang
- , Qinqin Ouyang
- & Rong Liu
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Article
| Open AccessRIPK1 regulates starvation resistance by modulating aspartate catabolism
RIPK1 is critical for normal development and cell death. Here, the authors identify a metabolic role for RIPK1 in aspartate homeostasis, as increased aspartate levels in RIPK1-deficient cells inhibits starvation-induced autophagy by ULK1.
- Xinyu Mei
- , Yuan Guo
- & Zheng-Jiang Zhu