Atg9 Vesicles Recruit Vesicle-tethering Proteins Trs85 and Ypt1 to the Autophagosome Formation Site

Kakuta, Soichiro; Yamamoto, Hayashi; Negishi, Lumi; Kondo-Kakuta, Chika; Hayashi, Nobuhiro; Ohsumi, Yoshinori

doi:10.1074/jbc.m112.411454

Cited by 107 publications

(117 citation statements)

References 45 publications

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“…For example, ATG9 is able to recruit the vesicle tethering machinery, TRAPPIII complex and Ypt1, to the PAS whereas absence of ATG9 impairs the trafficking of Trs85 or Ypt1 onto the autophagosome membrane (44,45). It has also been shown that UVRAG, another component of the ER tethering complex, works together with the PI3K complex to mobilize ATG9 translocation during autophagosome formation (46).…”

Section: Discussionmentioning

confidence: 99%

ATG9 regulates autophagosome progression from the endoplasmic reticulum in Arabidopsis

Zhuang

Chung

Cui

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

213

162

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Autophagy is a conserved pathway for bulk degradation of cytoplasmic material by a double-membrane structure named the autophagosome. The initiation of autophagosome formation requires the recruitment of autophagy-related protein 9 (ATG9) vesicles to the preautophagosomal structure. However, the functional relationship between ATG9 vesicles and the phagophore is controversial in different systems, and the molecular function of ATG9 remains unknown in plants. Here, we demonstrate that ATG9 is essential for endoplasmic reticulum (ER)-derived autophagosome formation in plants. Through a combination of genetic, in vivo imaging and electron tomography approaches, we show that Arabidopsis ATG9 deficiency leads to a drastic accumulation of autophagosome-related tubular structures in direct membrane continuity with the ER upon autophagic induction. Dynamic analyses demonstrate a transient membrane association between ATG9 vesicles and the autophagosomal membrane during autophagy. Furthermore, trafficking of ATG18a is compromised in atg9 mutants during autophagy by forming extended tubules in a phosphatidylinositol 3-phosphatedependent manner. Taken together, this study provides evidence for a pivotal role of ATG9 in regulating autophagosome progression from the ER membrane in Arabidopsis.O ne long-lasting question regarding autophagosome biogenesis is its membrane origin (1). The initiation site for autophagosomes is termed the preautophagosomal structure or phagophore assembly site (PAS). However, the source of the phagophore membrane remains controversial in different systems, and exactly how the phagophore is initiated from its membrane origin is still unclear. The core autophagy-related (ATG) machinery regulates phagophore assembly in a spatiotemporally coordinated manner whereas some of the ATG components will disassociate from the completed autophagosome and some are turned over together with the autophagosome (1-3).As the sole transmembrane protein, autophagy-related protein 9 (ATG9) has long been suggested to provide a lipid/membrane source for autophagosome formation because ATG9-deficient mutants in yeast or mammal fail to form autophagosomes (4, 5). Although ATG9 is conserved in all eukaryotes (6), it seems that ATG9 might perform its function divergently in different systems. In yeast, ATG9 participates in an early step by shuttling from a non-PAS site to the PAS site and supports an assembly model for yeast autophagosome biogenesis (4). In contrast, mammalian ATG9 is not stably incorporated into the isolation membrane or autophagosomes but is instead transiently associated with the omegasome, a phosphatidylinositol 3-phosphate (PI3P)-enriched endoplasmic reticulum (ER) subdomain (5). Cryomicroscopy studies have shown a close association between ATG9 vesicles and the omegasome structure (7), together with the presence of ATG9 on tubulovesicular membranes surrounding autophagosomes (5). A recent finding by livecell imaging indicates that autophagosome formation occurs where ATG9 vesicles coalesce with the ER ...

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Section: Discussionmentioning

confidence: 99%

ATG9 regulates autophagosome progression from the endoplasmic reticulum in Arabidopsis

Zhuang

Chung

Cui

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

213

162

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“…Immunoelectron microscopy analysis in another study detected Atg9 in clusters of small vesicles and tubules, and it was proposed that the isolation membrane may be initiated by the fusion of these clustered vesicles/tubules [89]. The Atg9 vesicle fusion mechanism may involve the yeast Rab protein Ypt1 and its GEF complex (the TRAPP III complex), which are required for autophagy and were identified in purified Atg9 vesicles [90,91]. In addition, SNARE proteins required for autophagosome formation in yeast have also been implicated in Atg9 vesicle fusion [92].…”

Section: Atg9 Vesicles As a Membrane Sourcementioning

confidence: 99%

A current perspective of autophagosome biogenesis

2013

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Autophagy is a bulk degradation system induced by cellular stresses such as nutrient starvation. Its function relies on the formation of double-membrane vesicles called autophagosomes. Unlike other organelles that appear to stably exist in the cell, autophagosomes are formed on demand, and once their formation is initiated, it proceeds surprisingly rapidly. How and where this dynamic autophagosome formation takes place has been a long-standing question, but the discovery of Atg proteins in the 1990's significantly accelerated our understanding of autophagosome biogenesis. In this review, we will briefly introduce each Atg functional unit in relation to autophagosome biogenesis, and then discuss the origin of the autophagosomal membrane with an introduction to selected recent studies addressing this problem.

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“…The TRAPPIII complex associates withSec23, an integral component of COPII, and is a GTP Exchange Factor (GEF) of a small GTPase Ypt1 in yeast. Therefore COPII vesicles and Ypt1 are recruited to the PAS, where COPII vesicles supply membrane and Ypt1 regulates vesicular events [50,[74][75][76]. Furthermore, it is proposed that the TRAPPIII complex may also be a tether to facilitate heterotypic fusion between an Atg9 vesicle and a COPII vesicle in the PAS [50,77].…”

Section: Converging On the Pasmentioning

confidence: 99%

“…Together with the C-terminal EAT domain of Atg1,which senses membrane curvature, the Atg17/Atg29/Atg31 complex dimerizes and may act as a tether for two Atg9 vesicles to facilitate homotypic fusion possibly via SNARE proteins [52,65,73]. In addition to theAtg1/Atg13/ Atg17/Atg29/Atg31 complex, another tethering complex, the transport protein particle III (TRAPPIII), also translocate to the PAS through direct association with Atg9 and Atg17 via Trs85, a specific subunit of TRAPPIII [74,75]. The TRAPPIII complex associates withSec23, an integral component of COPII, and is a GTP Exchange Factor (GEF) of a small GTPase Ypt1 in yeast.…”

Section: Converging On the Pasmentioning

confidence: 99%

Preparing the Membrane for Autophagosome Biogenesis

Wilz

Ge²

2014

Cell Dev Biol

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EditorialAutophagy is a fundamental strategy eukaryotic cells employ for bulk turnover of cytoplasmic components to maintain cellular homeostasis. At the organismal level, autophagy is involved in a variety of physiological processes such as development, metabolism and immunity. Dysfunctional autophagy has been implicated in numerous human disorders including cancer, neurodegeneration, aging, infection and metabolic disease [1][2][3].A key step of autophagy is the formation of a cup-shaped membrane precursor, called the phagophore, that engulfs part of the cytoplasm by membrane expansion to seal into a double membrane vesicle, termed the autophagosome. Fusion of the autophagosome with the lysosome leads to the degradation of the cytoplasmic components followed by release of the hydrolyzed products for material recycling [4][5][6][7].To build an autophagosome, a hierarchical cascade of the autophagy related(ATG) proteins is required to assemble a cradle, termed the phagophore assembly site (PAS), in a sub-domain of the endoplasmic reticulum (ER) in mammalian cells or near the vacuole (a functional equivalent of the lysosome) in yeast [5,[8][9][10][11][12][13][14]. In addition, substantial membrane mobilization from multiple locations, including ATG9-vesicles, the Golgi, the ER-Golgi intermediate compartment (ERGIC), ER exit sites(ERES), the plasma membrane (PM) and mitochondria, is necessary to deliver lipids and protein components to the PAS for autophagy initiation and phagophore growth [6,15,16]. Below, we briefly discuss the latest knowledge about how membranes are mobilized under autophagic conditions as well as how these membranes converge in the PAS for nucleating the phagophore precursor. Mobilizing the ATG9 vesiclesAutophagosome biogenesis begins with a membrane nucleation step at the PAS [12,14]. One factor essential for phagophore nucleation is ATG9, a multiple transmembrane protein [17][18][19][20]. In yeast, Atg9 cycles between the Trans-Golgi Network (TGN), mitochondria, the PAS and some distinct tubulovesicular peripheral structures [21][22][23][24][25]. Under starvation conditions, these peripheral compartments become highly dynamic reflecting an increased membrane exchange between these structures and the PAS [25]. Mobilization of Atg9 vesicles from the TGN to the peripheral structures is crucial for subsequent delivery of Atg9 vesicles to the PAS for phagophore nucleation [24,25]. This process requires protein complex formation of Atg9 with two partners, Atg23 and Atg27, as well as the self-dimerization of Atg9 [25][26][27][28]. It has been proposed that proper stoichiometric formation of the Atg9/ Atg23/Atg27 complex facilitates the clustering and sorting of Atg9 into a specific sub-domain in the TGN, which is essential for the generation of the tubulovesicular structure as an intermediate station for the delivery of Atg9 to the PAS [27].A similar cycling of ATG9 between the TGN and certain peripheral compartments also occurs in mammalian cells [29]. These peripheral structures are a combinatio...

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Atg9 Vesicles Recruit Vesicle-tethering Proteins Trs85 and Ypt1 to the Autophagosome Formation Site

Cited by 107 publications

References 45 publications

ATG9 regulates autophagosome progression from the endoplasmic reticulum in Arabidopsis

ATG9 regulates autophagosome progression from the endoplasmic reticulum in Arabidopsis

A current perspective of autophagosome biogenesis

Preparing the Membrane for Autophagosome Biogenesis

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