Atg2/TRAPPIII-Ypt1 axis: deciphering the phagophore-ERES connection

De novo generation of membrane contact sites (MCSs) between the nascent phagophore and the endoplasmic reticulum (ER), particularly the ER exit sites (ERES), are crucial for autophagy as they provide the lipids necessary for the phagophore expansion into an autophagosome. Our recent study provides insights into the mechanism involved in the formation of phagophore-ERES MCSs and uncovers how this event synchronizes the factors involved in phagophore expansion. We revealed that the TRAPPIII complex, the guanine nucleotide exchange factor of the Rab GTPase Ypt1, and the lipid transfer protein Atg2 participate in the phagophore-ERES association. We also show that establishment of phagophore-ERES MCSs leads to TRAPPIII activation and subsequent Ypt1 recruitment onto the phagophore. The presence of active Ypt1 on the growing phagophore enhances local biosynthesis of phosphatidylinositol-3-phosphate (PtdIns3P), triggering the recruitment of the PtdIns3P-effectors Atg18 and Atg21, which play a central role in phagophore expansion. These findings suggest that generation of phagophore-ERES MCSs is one of the signals initiating phagophore expansion.Abbreviations: Atg, autophagy related; ER, endoplasmic reticulum; ERES, ER exit sites; GEF, guanine nucleotide exchange factor; MCS, membrane contact site; PAS, phagophore assembly site; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns3K, phosphatidylinositol 3-kinase; SNARE, soluble NSF attachment protein receptor; TOR, Target of Rapamycin; WIPI, WD-repeat domain, phosphoinositide interacting.