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 endolysosomal perinuclear positioning and transport dynamics. Here, we report that the ubiquitin conjugating enzyme UBE2J1, also anchored in the ER membrane, partners with RNF26 in this context, and that the cellular activity of the resulting E2/E3 pair is localized in a perinuclear ER subdomain and 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 promotes the trafficking of activated EGFR to lysosomes and facilitates the termination of EGF-induced AKT signaling.

内溶酶体系统具有多种细胞功能，其中许多功能是通过与其他细胞器的相互作用来调节的。特别是，ER 对内体和溶酶体的组织和运动施加时空限制。我们最近将 ER 跨膜 E3 泛素连接酶 RNF26 描述为内溶酶体核周定位和运输动力学的调节剂。在这里，我们报告泛素结合酶 UBE2J1，也锚定在 ER 膜中，在这种情况下与 RNF26 合作，并且所得 E2/E3 对的细胞活性定位于核周 ER 亚结构域并由跨膜相互作用支持。通过在赖氨酸 435 上修饰 SQSTM1/p62，嵌入 ER 的 UBE2J1/RNF26 泛素化复合物募集内体适配器以将其同源囊泡固定在细胞的核周区域。由此产生的时空区室化促进活化的 EGFR 向溶酶体的运输，并促进 EGF 诱导的 AKT 信号传导的终止。