Preparing the Membrane for Autophagosome Biogenesis

Abstract

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...