Vimentin intermediate filaments organize organellar architecture in response to ER stress

Compartmentalization of organelles in space and time affects their functional state and enables higher order regulation of essential cellular processes. How organellar residence is maintained in a defined area of the cell remains poorly understood. In this study, we uncover a new role for intermediate filaments in the maintenance of organellar architecture and dynamics, which is executed through a functional connection between Vimentin and the ER-embedded ubiquitin ligase ring finger protein 26 (RNF26). While the ubiquitin ligase function of RNF26 promotes perinuclear positioning of endolysosomes, its catalytically inactive mutant I382R preferentially binds Vimentin through the RNF26 C-terminal tail. Loss of either RNF26 or Vimentin redistributes endolysosomes throughout the cytosol and mobilizes ER membranes from the perinuclear ER towards the periphery. Furthermore, RNF26 and Vimentin control changes in ER morphology and organelle compartmentalization during ER stress. Collectively, we define a new function for Vimentin-containing intermediate filaments as anchors of a dynamic interplay between the ER and endosomes, critical to the integrity of the perinuclear ER and corresponding perinuclear endosomal cloud during homeostatic and stress conditions.