Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation

Knævelsrud, Helene; Søreng, Kristiane; Raiborg, Camilla; Håberg, Karin; Rasmuson, Fredrik; Brech, Andreas; Liestøl, Knut; Rusten, Tor Erik; Stenmark, Harald; Neufeld, Thomas P.; Carlsson, Sven R.; Simonsen, Anne

doi:10.1083/jcb.201205129

Cited by 158 publications

(202 citation statements)

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“…The lack of WIPI2‐ATG16L1 colocalisation is caused by a significant reduction of the number of ATG16L1 and WIPI2 puncta formed in response to starvation in the SNX18 KO cells compared to WT cells (Fig 2C and D). These data are in line with our previous studies, showing that the starvation‐induced colocalisation of ATG16L1 with the omegasome marker DFCP1 is reduced in SNX18‐depleted cells 26. In contrast, the number of WIPI2 spots was not reduced upon siRNA‐mediated depletion of SNX18, which could be explained by insufficient knockdown efficiency.…”

Section: Resultssupporting

confidence: 92%

“…As SNX18 promotes autophagy by generating TfR‐positive tubules positive for ATG16L1 and GFP‐LC3 26, we asked whether SNX18 may also regulate trafficking of ATG9A. Indeed, endogenous ATG9A colocalised with endogenous SNX18 (Fig EV1A) and was detected along the membrane structures induced by overexpression of SNX18 in HEK293A cells (Fig 1A).…”

Section: Resultsmentioning

confidence: 98%

“…Interestingly, ATG16L1 did not accumulate in the ATG9A‐ and TfR‐positive juxtanuclear recycling endosome compartment seen in SNX18 KO cells (Fig 2E), suggesting that ATG16L1 could exit the recycling endosomes separately from ATG9A or that association of ATG16L1 with the recycling endosome membrane is SNX18 dependent. We have previously demonstrated a direct interaction between SNX18 and ATG16L1 26, but further experiments and analysis of the relationship between ATG16L1 and SNX18 are needed to elucidate whether this interaction is responsible for the observed role of SNX18 in ATG16L1 recruitment to WIPI2‐positive structures. A recent publication shows that lack of the sphingomyelin phosphodiesterase 1 (SMPD1) also leads to accumulation of ATG9A in juxtanuclear recycling endosomes without a corresponding accumulation of ATG16L1 9.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, an interaction of ATG9A with AP‐4 in the TGN was found to facilitate its transport to peripheral compartments and depletion of AP‐4 to affect normal autophagosome formation 37. SNX18 contains an AP‐1 binding motif (WDDEW) in its unstructured LC region, which also mediates its interaction with LC3 and GABARAP proteins 26, 30. Here, we show that the SH3 domain of SNX18 recruits Dynamin‐2 to mediate formation of ATG9A vesicles from recycling endosomes, but whether or not this involves binding of ATG9 and/or SNX18 to any AP complex requires further investigation.…”

Section: Resultsmentioning

confidence: 99%

“…The phagophore expands by receiving membrane input through vesicle transport or membrane contact sites from different membrane sources, including ER‐exit sites (ERES) and the ER–Golgi intermediate compartment (ERGIC) 18, 19, 20, the Golgi apparatus 21, 22, mitochondria 23, 24 and the plasma membrane 21, 22, 25. Recently, it has become evident that recycling endosomes also play an important role during autophagosome biogenesis and both ATG16L1 and ATG9A traffic from the plasma membrane to recycling endosomes on their way to sites of autophagosome formation 7, 8, 9, 10, 26. We recently identified the PX‐BAR‐containing protein sorting nexin 18 (SNX18) as a positive regulator of autophagy 26.…”

Section: Introductionmentioning

confidence: 99%

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SNX 18 regulates ATG 9A trafficking from recycling endosomes by recruiting Dynamin‐2

et al. 2018

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Trafficking of mammalian ATG9A between the Golgi apparatus, endosomes and peripheral ATG9A compartments is important for autophagosome biogenesis. Here, we show that the membrane remodelling protein SNX18, previously identified as a positive regulator of autophagy, regulates ATG9A trafficking from recycling endosomes. ATG9A is recruited to SNX18‐induced tubules generated from recycling endosomes and accumulates in juxtanuclear recycling endosomes in cells lacking SNX18. Binding of SNX18 to Dynamin‐2 is important for ATG9A trafficking from recycling endosomes and for formation of ATG16L1‐ and WIPI2‐positive autophagosome precursor membranes. We propose a model where upon autophagy induction, SNX18 recruits Dynamin‐2 to induce budding of ATG9A and ATG16L1 containing membranes from recycling endosomes that traffic to sites of autophagosome formation.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SNX 18 regulates ATG 9A trafficking from recycling endosomes by recruiting Dynamin‐2

et al. 2018

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Phosphoinositide‐binding proteins in autophagy

Lystad

Simonsen

2016

FEBS Letters

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Edited by Wilhelm JustPhosphoinositides represent a very small fraction of membrane phospholipids, having fast turnover rates and unique subcellular distributions, which make them perfect for initiating local temporal effects. Seven different phosphoinositide species are generated through reversible phosphorylation of the inositol ring of phosphatidylinositol (PtdIns). The negative charge generated by the phosphates provides specificity for interaction with various protein domains that commonly contain a cluster of basic residues. Examples of domains that bind phosphoinositides include PH domains, WD40 repeats, PX domains, and FYVE domains. Such domains often display specificity toward a certain species or subset of phosphoinositides. Here we will review the current literature of different phosphoinositide-binding proteins involved in autophagy.Keywords: autophagy; FYVE; PH; phosphoinositide; PX AutophagyAutophagy is the process by which cellular components are transported to the lysosome (or the yeast vacuole) for degradation to provide cellular homeostasis and quality control. There are three main forms of autophagy, namely microautophagy, which involves a direct engulfment of cytosolic cargo by the endosomal or lysosomal/vacuolar membrane, chaperone-mediated autophagy (CMA), involving lysosomal translocation of cytosolic protein cargo, and macroautophagy, a vesicle transport pathway where cargo is sequestered into double-membrane autophagosomes which undergo fusion with endosomes and/or the lysosome/vacuole. Autophagy is induced upon cellular stress (e.g., starvation) to facilitate cell survival by providing building blocks that can be used to produce essential molecules and generate energy. However, autophagy also serves an important quality control function under basal conditions by selective clearance of damaged or dysfunctional cellular components [1].Macroautophagy (hereafter autophagy) involves nucleation of a phagophore membrane (also called the isolation membrane) from specific phosphatidyl inositol 3-phosphate (PtdIns3P)-enriched structures, called the phagophore assembly site (PAS, a peri-vacuolar structure) in yeast and the omegasome (associated with the endoplasmic reticulum, ER) in mammals. Typically, there is only a single PAS in yeast, while several ER-associated omegasomes are detected upon Abbreviations ALFY, autophagy-linked FYVE protein; Arf6, adenosine diphosphate ribosylation factor 6; ATG, autophagy-related; BATS, biotin and thiamin synthesis-associated domain; Cvt, cytoplasm-to-vacuole; DFCP1, double FYVE-containing protein 1; ER, endoplasmic reticulum; FYCO1, FYVE and coiled-coil domain-containing 1; GRAM, glycosyltransferases Rab-like GTPase activators and myotubularins; HOPS, homotypic fusion and protein sorting; Hsv2, homologous with swollen vacuole phenotype 2; LIR, LC3-interacting region; MTMR3, myotubularin-related protein 3; mTORC1, mechanistic target of rapamycin complex 1; PA, phosphatidic acid; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide-dependent protein kinase ...

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Lysosome Biogenesis and Autophagy

Reggiori

Klumperman

2016

Lysosomes: Biology, Diseases, and Therapeutics

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Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation

Abstract: SNX18 promotes autophagosome formation by remodeling membranes and providing membrane to forming autophagosomes.

Cited by 158 publications

References 43 publications

SNX 18 regulates ATG 9A trafficking from recycling endosomes by recruiting Dynamin‐2

SNX 18 regulates ATG 9A trafficking from recycling endosomes by recruiting Dynamin‐2

Phosphoinositide‐binding proteins in autophagy

Lysosome Biogenesis and Autophagy

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