A Role for Macro-ER-Phagy in ER Quality Control

The endoplasmic-reticulum quality-control (erqc) system shuttles misfolded proteins for degradation by the proteasome through the well-defined er-associated degradation (erad) pathway. in contrast,very little is known about the role of autophagy in erqc. macro-autophagy,a collection of pathways that deliver proteins through autophagosomes (aps) for degradation in the lysosome (vacuole in yeast),is mediated by autophagy-specific proteins,atgs,and regulated by ypt/rab gtpases. until recently,the term er-phagy was used to describe degradation of er membrane and proteins in the lysosome under stress: either er stress induced by drugs or whole-cell stress induced by starvation. these two types of stresses induce micro-er-phagy,which does not use autophagic organelles and machinery,and non-selective autophagy. here,we characterize the macro-er-phagy pathway and uncover its role in erqc. this pathway delivers 20–50% of certain er-resident membrane proteins to the vacuole and is further induced to >90% by overexpression of a single integral-membrane protein. even though such overexpression in cells defective in macro-er-phagy induces the unfolded-protein response (upr),upr is not needed for macro-er-phagy. we show that macro-er-phagy is dependent on atgs and ypt gtpases and its cargo passes through aps. moreover,for the first time the role of atg9,the only integral-membrane core atg,is uncoupled from that of other core atgs. finally,three sequential steps of this pathway are delineated: atg9-dependent exit from the er en route to autophagy,ypt1- and core atgs-mediated pre-autophagsomal-structure organization,and ypt51-mediated delivery of aps to the vacuole. © 2015 lipatova,segev.