RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress

Abstract

Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear. Here, we identify vimentin intermediate filaments as perinuclear anchors for the ER and endolysosomes. We show that perinuclear vimentin filaments engage the ER‐embedded RING finger protein 26 (RNF26) at the C‐terminus of its RING domain. This restricts RNF26 to perinuclear ER subdomains and enables the corresponding spatial retention of endolysosomes through RNF26‐mediated membrane contact sites (MCS). We find that both RNF26 and vimentin are required for the perinuclear coalescence of the ERQC and its juxtaposition with proteolytic compartments, which facilitates efficient recovery from ER stress via the Sec62‐mediated ER‐phagy pathway. Collectively, our findings reveal a scaffolding mechanism that underpins the spatiotemporal integration of organelles during cellular proteostasis. image Response to proteotoxic stress requires remodeling of the endoplasmic reticulum (ER) into the ER quality control compartment (ERQC), which is degraded in endolysosomes upon return to homeostasis. Here, a direct interaction between the ER‐embedded E3 ubiquitin ligase RNF26 and vimentin is shown to mediate perinuclear ER/endolysosome contact sites and to promote Sec62‐mediated ER‐phagy. Vimentin directly interacts with a C‐terminal motif of inactive RNF26 in the ER membrane. The vimentin–RNF26 interaction controls the perinuclear organization of ER membrane sheets and the endosomal system. Vimentin and RNF26 control ER morphology in homeostatic and stressed conditions. RNF26 localizes to vimentin‐coordinated ERQC domains and interacts with endoplasmic reticulum‐associated degradation (ERAD) machinery.