Autophagy in inflammation, infection, and immunometabolism

Immunity, Journal Year: 2021, Volume and Issue: 54(3), P. 437 - 453

Published: March 1, 2021

Language: Английский

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The autophagic membrane tether ATG2A transfers lipids between membranes

eLife, Journal Year: 2019, Volume and Issue: 8

Published: July 4, 2019

An enigmatic step in de novo formation of the autophagosome membrane compartment is expansion precursor phagophore, which requires acquisition lipids to serve as building blocks. Autophagy-related 2 (ATG2), rod-shaped protein that tethers phosphatidylinositol 3-phosphate (PI3P)-enriched phagophores endoplasmic reticulum (ER), suggested be essential for phagophore expansion, but underlying mechanism remains unclear. Here, we demonstrate human ATG2A a lipid transfer protein. can extract from vesicles and unload them other vesicles. Lipid by more efficient between tethered than untethered The PI3P effectors WIPI4 WIPI1 associate stably PI3P-containing vesicles, thereby facilitating ATG2A-mediated tethering PI3P-free Based on these results, propose ATG2-mediated ER enables expansion.

Language: Английский

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Autophagy in metabolic disease and ageing

Nature Reviews Endocrinology, Journal Year: 2021, Volume and Issue: 17(11), P. 647 - 661

Published: Sept. 10, 2021

Language: Английский

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Mechanisms of Selective Autophagy

Annual Review of Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 37(1), P. 143 - 169

Published: June 21, 2021

Selective autophagy is the lysosomal degradation of specific intracellular components sequestered into autophagosomes, late endosomes, or lysosomes through activity selective receptors (SARs). SARs interact with autophagy-related (ATG)8 family proteins via sequence motifs called LC3-interacting region (LIR) in vertebrates and Atg8-interacting (AIMs) yeast plants. can be divided two broad groups: soluble membrane bound. Cargo substrate selection may independent dependent ubiquitin labeling cargo. In this review, we discuss mechanisms mammalian a focus on unifying principles employed recognition, interaction forming autophagosome LIR-ATG8 interactions, recruitment core for efficient formation substrate.

Language: Английский

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The Cargo Receptor NDP52 Initiates Selective Autophagy by Recruiting the ULK Complex to Cytosol-Invading Bacteria

Molecular Cell, Journal Year: 2019, Volume and Issue: 74(2), P. 320 - 329.e6

Published: March 7, 2019

Xenophagy, a selective autophagy pathway that protects the cytosol against bacterial invasion, relies on cargo receptors juxtapose bacteria and phagophore membranes. Whether phagophores are recruited from constitutive pool or generated de novo at prospective remains unknown. Phagophore formation in situ would require recruitment of upstream machinery to cargo. Here, we show that, essential for anti-bacterial autophagy, receptor NDP52 forms trimeric complex with FIP200 SINTBAD/NAP1, which subunits autophagy-initiating ULK TBK1 kinase complex, respectively. SINTBAD/NAP1 each independently via NDP52, as revealed by point mutations their respective binding sites, but only combined presence does xenophagy proceed. Such reveals how detection cargo-associated "eat me" signals, induction juxtaposition integrated higher eukaryotes.

Language: Английский

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STING induces LC3B lipidation onto single-membrane vesicles via the V-ATPase and ATG16L1-WD40 domain

The Journal of Cell Biology, Journal Year: 2020, Volume and Issue: 219(12)

Published: Nov. 5, 2020

Following the detection of cytosolic double-stranded DNA from viral or bacterial infection in mammalian cells, cyclic dinucleotide activation STING induces interferon β expression to initiate innate immune defenses. also LC3B lipidation, a classical but equivocal marker autophagy, that promotes cell-autonomous antiviral response arose before evolution pathway. We report lipidation onto single-membrane perinuclear vesicles mediated by ATG16L1 via its WD40 domain, bypassing requirement canonical upstream autophagy machinery. This process is blocked bafilomycin A1 binds and inhibits vacuolar ATPase (V-ATPase) SopF, effector catalytically modifies V-ATPase inhibit ATG16L1. These results indicate cGAS-STING pathway V-ATPase-dependent may mediate host defense, an unanticipated mechanism distinct double-membrane autophagosomes.

Language: Английский

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Autophagosome biogenesis comes out of the black box

Nature Cell Biology, Journal Year: 2021, Volume and Issue: 23(5), P. 450 - 456

Published: April 26, 2021

Language: Английский

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Mechanisms of nonvesicular lipid transport

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(3)

Published: Feb. 19, 2021

We have long known that lipids traffic between cellular membranes via vesicles but only recently appreciated the role of nonvesicular lipid transport. Nonvesicular transport can be high volume, supporting biogenesis rapidly expanding membranes, or more targeted and precise, allowing cells to alter levels specific in membranes. Most such probably occurs at membrane contact sites, where organelles are closely apposed, requires proteins (LTPs), which solubilize shield them from aqueous phase during their Some LTPs cup like shuttle monomers Others form conduits flow This review describes what we know about transfer mechanisms while also identifying many remaining unknowns: How do facilitate movement into require accessory for efficient vivo, how is directionality determined?

Language: Английский

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Beyond autophagy: LC3-associated phagocytosis and endocytosis

Science Advances, Journal Year: 2022, Volume and Issue: 8(43)

Published: Oct. 26, 2022

Noncanonical functions of the autophagy machinery in pathways including LC3-associated phagocytosis and endocytosis have garnered increasing interest both normal physiology pathobiology. New discoveries over past decade noncanonical uses these distinct molecular mechanisms led to robust investigation into roles single-membrane LC3 lipidation. now been implicated regulation multiple processes ranging from debris clearance, cellular signaling, immune inflammation. Accumulating evidence is demonstrating a variety disease states host-pathogen responses, autoimmunity, cancer, neurological neurodegenerative pathologies. Here, we broadly summarize differences mechanistic between LAP LANDO highlight some key innate function, inflammation, pathology.

Language: Английский

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ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(22), P. 4324 - 4339.e8

Published: Nov. 1, 2022

ATG9A and ATG2A are essential core members of the autophagy machinery. is a lipid scramblase that allows equilibration lipids across membrane bilayer, whereas facilitates flow between tethered membranes. Although both have been functionally linked during formation autophagosomes, molecular details consequences their interaction remain unclear. By combining data from peptide arrays, crosslinking, hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, we propose model ATG9A-2A complex. Using this integrative structure modeling approach, identify several interfaces mediating would allow direct transfer into lipid-binding perpendicular branch ATG9A. Mutational analyses combined functional activity assays demonstrate importance for autophagy, thereby shedding light on protein complex at heart autophagy.

Language: Английский

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