9.A.15.1.1
Autophagy-related protein complex of Saccharomyces cerevisiae (Munakata and Klionsky, 2010).  Different levels of autophagy activity reflect differences in autophagosome formation, correlating with the delivery of Atg9 to the PAS. Phosphorylation regulates the Atg9 interaction with Atg23 and Atg27 (Feng et al. 2016).  Atg27 is required for Atg9 cycling, and shuttles between the pre-autophagosomal structure, mitochondria, and the Golgi complex (Yen et al. 2007). Atg9 colocalizes with Atg2 at the expanding edge of the isolation membrane (IM), where Atg2 receives phospholipids from the endoplasmic reticulum (ER). Matoba et al. 2020 reported that yeast and human Atg9 are lipid scramblases that translocate phospholipids between outer and inner leaflets of liposomes in vitro. Cryo-EM of fission yeast Atg9 revealed a homotrimer, with two connected pores forming a path between the two membrane leaflets: one pore, located at a protomer, opens laterally to the cytoplasmic leaflet; the other, at the trimer center, traverses the membrane vertically. Mutation of residues lining the pores impaired IM expansion and autophagy activity in yeast and abolished Atg9's ability to transport phospholipids between liposome leaflets. Thus, phospholipids delivered by Atg2 are translocated from the cytoplasmic to the luminal leaflet by Atg9, thereby driving autophagosomal membrane expansion. Guardia et al. 2020 solved a high-resolution cryoEM structure of the ubiquitously expressed human ATG9A isoform. ATG9A is a domain-swapped homotrimer with a unique fold, and has an internal network of branched cavities. The functional importance of the cavity-lining residues which could serve as conduits for transport of hydrophilic moieties, such as lipid headgroups, across the bilayer has been suggested (Guardia et al. 2020). Transbilayer phospholipid movement that is mediated by Atg9 is involved in the biogenesis of autophagosomes (Orii et al. 2021).