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

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.

Automated summary

Proteotoxic stress triggers remodeling of the endoplasmic reticulum (ER) membrane, resulting in the formation of a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Vimentin intermediate filaments act as anchors, recruiting the RING finger protein 26 (RNF26) to the perinuclear ER subdomains and facilitating the spatial retention of endolysosomes. RNF26 and vimentin are both essential for the formation of the perinuclear ERQC and its association with proteolytic compartments, allowing efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway.