ER exit sites are physical and functional core autophagosome biogenesis components

Graef, Martin; Friedman, Jonathan R.; Graham, Christopher I.; Babu, Mohan; Nunnari, Jodi

doi:10.1091/mbc.e13-07-0381

Cited by 347 publications

(438 citation statements)

References 74 publications

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“…In mammalian cells and yeast, ATG5 was mainly found homogenously distributed onto early phagophores, shifting to a preferential localization on the whole outer surface of maturing phagophores 7,21,22 . However, a recent study in yeast describes a dot-like localization of Atg5 juxtaposed to the Atg8 signal 41 , which is consistent with our observation of a fine regulation of the spatial disposition of ATG5 on the phagophore/isolation membrane. Although our findings could reflect plant-specific aspects of phagophore formation, the possibility that the toroidal disposition of ATG5 has not been detected yet in other models for technical reasons cannot be formally excluded.…”

Section: Discussionsupporting

confidence: 92%

ATG5 defines a phagophore domain connected to the endoplasmic reticulum during autophagosome formation in plants

Bars

Marion

Borgne³

et al. 2014

Nat Commun

125

103

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Autophagosomes are the organelles responsible for macroautophagy and arise, in yeast and animals, from the sealing of a cup-shaped double-membrane precursor, the phagophore. How the phagophore is generated and grows into a sealed autophagosome is still not clear in detail, and unknown in plants. This is due, in part, to the scarcity of structurally informative, real-time imaging data of the required protein machinery at the phagophore formation site. Here we find that in intact living Arabidopsis tissue, autophagy-related protein ATG5, which is essential for autophagosome formation, is present at the phagophore site from early, sub-resolution stages and later defines a torus-shaped structure on a flat cisternal early phagophore. Movement and expansion of this structure are accompanied by the underlying endoplasmic reticulum, suggesting tight connections between the two compartments. Detailed real-time and 3D imaging of the growing phagophore are leveraged to propose a model for autophagosome formation in plants.

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Section: Discussionsupporting

confidence: 92%

ATG5 defines a phagophore domain connected to the endoplasmic reticulum during autophagosome formation in plants

Bars

Marion

Borgne³

et al. 2014

Nat Commun

125

103

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“…Interestingly, Atg9 and the Atg2-Atg18 complex accumulated at the edge of the isolation membrane. Consistent with this, Graef et al identified protein-protein interactions between Atg and COPII coat proteins using a proteomics approach, and showed that the edge of the isolation membrane is located in close proximity to the ER exit sites [77]. Although the exact mechanism of how ER exit sites contribute to autophagosome biogenesis has yet to be elucidated, it has previously been shown that ER-toGolgi trafficking plays an important role in autophagosome biogenesis both in yeast [78,79] and in mammals [80,81].…”

Section: Er Exit Sitesmentioning

confidence: 79%

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 role of COPII in mobilizing the membrane for autophagosome biogenesis was also implicated in two other studies performed in yeast; one investigating macroautophagy and the other focusing on the cytoplasm to vacuole targeting (Cvt) pathway, a selective form of autophagy in yeast [45][46][47]. These studies indicate a physiological and functional link between the COPII-enriched spot, the ERES (a functional equivalent of both the ERGIC and ERES of mammalian cells) and the PAS in yeast.…”

Section: Mobilizing the Er-derived Membranes Through Copiimentioning

confidence: 84%

“…These studies indicate a physiological and functional link between the COPII-enriched spot, the ERES (a functional equivalent of both the ERGIC and ERES of mammalian cells) and the PAS in yeast. As another support of this notion, depletion of COPII components has been shown to compromise autophagy in both yeast and mammalian cells [44,45,[48][49][50].…”

Section: Mobilizing the Er-derived Membranes Through Copiimentioning

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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ER exit sites are physical and functional core autophagosome biogenesis components

Abstract: ERES function is required for assembly of the autophagy machinery immediately downstream of the Atg1 kinase complex and is associated with formation of autophagosomes at every stage of the process. ERES are core components of the autophagy machinery for the biogenesis of autophagosomes.

Cited by 347 publications

References 74 publications

ATG5 defines a phagophore domain connected to the endoplasmic reticulum during autophagosome formation in plants

ATG5 defines a phagophore domain connected to the endoplasmic reticulum during autophagosome formation in plants

A current perspective of autophagosome biogenesis

Preparing the Membrane for Autophagosome Biogenesis

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