The ER-embedded UBE2J1/RNF26 ubiquitylation complex in spatio-temporal control of the endolysosomal pathwayThe ER-embedded UBE2J1/RNF26 ubiquitylation complex in spatio-temporal control of the endolysosomal pathway

The endolysosomal system fulfills a wide variety of cellular functions, many of which are modulated through interactions with other organelles. In particular, the ER exerts spatiotemporal constraints on the organization and motility of endosomes and lysosomes. We have recently described the ER transmembrane E3 ubiquitin ligase RNF26 as a regulator of perinuclear positioning and transport dynamics of the endolysosomal network. We now report that the ubiquitin conjugating enzyme UBE2J1, also anchored in the ER membrane, collaborates with RNF26 in this context, and that the cellular activity of this E2/E3 pair, localized in a perinuclear ER subdomain, is supported by transmembrane interactions. Through modification of SQSTM1/p62 on lysine 435, the ER-embedded UBE2J1/RNF26 ubiquitylation complex recruits endosomal adaptors to immobilize their cognate vesicles in the perinuclear region of the cell. The resulting spatiotemporal compartmentalization of the endolysosomal system promotes trafficking of activated EGFR to the late compartments and facilitates cessation of downstream AKT signaling.