ATG2 transports lipids to promote autophagosome biogenesis

Valverde, Diana P.; Yu, Shenliang; Boggavarapu, Rajendra; Kumar, Nikit; Lees, Joshua A.; Walz, Thomas; Reinisch, Karin M; Melia, Thomas J.

doi:10.1083/jcb.201811139

Cited by 420 publications

(540 citation statements)

References 35 publications

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“…45 Moreover, ATG2A was shown to localize to autophagosome-ER contact sites in mammalian cells. 46 These observations are consistent with those observed for yeast Atg2, suggesting that the LT and MT activities of Atg2 and their role in autophagy are evolutionarily conserved.…”

Section: Discovery Of the Phospholipid Transfer Activity Of Atg2supporting

confidence: 86%

“…In vitro LT activity was also confirmed for human ATG2A and ATG2B (Osawa and Noda, unpublished observation). ATG2A bridges SUVs and transfers phospholipids between them, which is accelerated by the addition of PI3P together with WIPI proteins .…”

Section: Discovery Of the Phospholipid Transfer Activity Of Atg2supporting

confidence: 79%

“…ATG2A bridges SUVs and transfers phospholipids between them, which is accelerated by the addition of PI3P together with WIPI proteins . Moreover, ATG2A was shown to localize to autophagosome–ER contact sites in mammalian cells . These observations are consistent with those observed for yeast Atg2, suggesting that the LT and MT activities of Atg2 and their role in autophagy are evolutionarily conserved.…”

Section: Discovery Of the Phospholipid Transfer Activity Of Atg2mentioning

confidence: 99%

“…, right). Indeed, recent Cryo‐EM analysis of ATG2A at 15 Å resolution proposed the existence of hydrophobic grooves or cavities throughout the rod structure although their consecutiveness remained elusive . A long hydrophobic groove has been observed in other LT protein complexes.…”

Section: Proposed Mechanism Of Phospholipid Transfer Mediated By Atg2mentioning

confidence: 99%

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Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

Osawa

Noda

2019

Protein Science

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The degradation of cytoplasmic components via autophagy is crucial for intracellular homeostasis. In the process of autophagy, a newly synthesized isolation membrane (IM) is developed to sequester degradation targets and eventually the IM seals, forming an autophagosome. One of the most poorly understood autophagy‐related proteins is Atg2, which is known to localize to a contact site between the edge of the expanding IM and the exit site of the endoplasmic reticulum (ERES). Recent advances in structural and biochemical analyses have been applied to Atg2 and have revealed it to be a novel multifunctional protein that tethers membranes and transfers phospholipids between them. Considering that Atg2 is essential for the expansion of the IM that requires phospholipids as building blocks, it is suggested that Atg2 transfers phospholipids from the ERES to the IM during the process of autophagosome formation, suggesting that lipid transfer proteins can mediate de novo organelle biogenesis.

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Section: Discovery Of the Phospholipid Transfer Activity Of Atg2supporting

confidence: 86%

Section: Discovery Of the Phospholipid Transfer Activity Of Atg2supporting

confidence: 79%

Section: Discovery Of the Phospholipid Transfer Activity Of Atg2mentioning

confidence: 99%

Section: Proposed Mechanism Of Phospholipid Transfer Mediated By Atg2mentioning

confidence: 99%

See 2 more Smart Citations

Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

Osawa

Noda

2019

Protein Science

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“…ATG3 regulates the transfer of PE to ATG8, with ATG7 again acting upstream as the E1-like activating enzyme in this process [2]. Importantly, it is anticipated that lipids from diverse sources within the cell become subsumed by or transferred into the expanding isolation membrane, to meet the acute demand for membrane supply/turnover during nutrient stress [3,4]. Candidate donor sources include: the ER [5]; ER exit sites/ERGIC [6]; the plasma membrane [7]; mitochondria [8]; COPII vesicles [9]; and the Rab11-positive recycling endosome [10].…”

Section: Introductionmentioning

confidence: 99%

The ATG5 Interactome Links Clathrin Vesicular Trafficking With The ATG8 Lipidation Machinery For Autophagosome Assembly

Baines

Lane

2019

Preprint

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Autophagosome formation involves the sequential actions of conserved ATG family proteins that regulate the lipidation of the ubiquitin-like modifier ATG8 at the nascent isolation membrane.Although the molecular steps driving this process are well understood, the source of membranes supplied for the expanding autophagosome and their mode of delivery remain uncertain. Here, we have used quantitative SILAC-based proteomics to identify proteins that associate with the ATG12~ATG5 conjugate that is crucial for ATG8 lipidation. Our datasets reveal a strong enrichment of regulators of clathrin-mediated vesicular trafficking, including clathrin heavy and light chains, and several clathrin adaptors. Also identified were PIK3C2A (a phosphoinositide 3-kinase involved in clathrin-mediated endocytosis) and HIP1R (a component of clathrin vesicles), and the absence of either of these proteins caused defects in autophagic flux in cell-based starvation assays. To determine whether the ATG12~ATG5 conjugate reciprocally influences trafficking within the endocytic compartment, we captured the cell surface proteomes of autophagycompetent and autophagy-incompetent mouse embryonic fibroblasts under fed and starved conditions. Proteins whose surface expression increased contingent on autophagic capability included EPHB2, SLC12A4, and JAG1. Those whose surface expression was decreased included CASK, SLC27A4 and LAMP1. These data provide evidence for direct regulatory coupling between the ATG12~ATG5 conjugate and the clathrin membrane trafficking system, and suggest candidate membrane proteins whose trafficking within the cell may be modulated by the autophagy machinery.

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Hijacking intracellular membranes to feed autophagosomal growth

Staiano

Zappa

2019

FEBS Letters

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Autophagy is widely considered as a housekeeping mechanism that enables cells to survive stress conditions and, in particular, nutrient deprivation. Autophagy begins with the formation of the phagophore that expands and closes around cytosolic material and damaged organelles destined for degradation. The execution of this complex machinery is guaranteed by the coordinated action of more than 40 ATG (autophagy‐related) proteins that control the entire process at different stages from the biogenesis of the autophagosome to cargo sequestration and fusion with lysosomes. Autophagosome biogenesis occurs at multiple intracellular sites, such as the endoplasmic reticulum (ER) and the plasma membrane. Soon after the formation of the phagophore, the nascent autophagosome progressively grows in size and ultimately closes by recruiting intracellular membranes. In this review, we focus on the contribution of three membrane sources – the ER, the ER–Golgi intermediate compartment, and the Golgi complex – to autophagosome biogenesis and expansion. We also highlight the interplay between the secretory pathway and autophagy in cells when nutrients are scarce.

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ATG2 transports lipids to promote autophagosome biogenesis

Abstract: Valverde et al. show that the autophagy protein ATG2 functions in autophagosome biogenesis by transferring lipids at ER–autophagosome contact sites.

Cited by 420 publications

References 35 publications

Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

The ATG5 Interactome Links Clathrin Vesicular Trafficking With The ATG8 Lipidation Machinery For Autophagosome Assembly

Hijacking intracellular membranes to feed autophagosomal growth

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