Vimentin intermediate filaments organize organellar architecture in response to ER stress

Abstract

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.SynopsisThe perinuclear area hosts a wide variety of cellular organelles, and their interaction with the ER governs essential cellular processes. To spatiotemporally organize endosomes and ER in the perinuclear region, the ER-embedded E3 ubiquitin ligase RNF26 interacts with Vimentin to physically link the perinuclear ER membrane with the intermediate filament cytoskeleton. As a result, Vimentin ensures perinuclear RNF26 retention, which in turn controls the perinuclear location of ER membranes and endosomes, which can be affected during stressed conditions. Vimentin interacts with inactive RNF26 in the ER membraneRNF26 by virtue of the Vimentin interaction controls perinuclear organization of ER membranes and the endosomal systemVimentin immobilizes ER membranes in the perinuclear areaVimentin and RNF26 compartmentalize organelles in the perinuclear region during ER stressWe define a new function of Vimentin intermediate filaments in the control of the perinuclear endosomal and ER organization

Vimentin intermediate filaments provide structural stability to the mammalian Golgi apparatus

“…How vimentin IFs provide support to the Golgi remain to be determined, but an attractive hypothesis is that they form a cage or meshwork around the organelle, which provides a mechano-protective function. This would be analogous to what has been reported for the nucleus and other cytoplasmic organelles (Cremer et al, 2022; Etienne-Manneville, 2018). The Golgi ribbon, by virtue of its localization adjacent to the nucleus, may be embedded within the IF meshwork that forms a cage around the nucleus (Cremer et al, 2022; Etienne-Manneville, 2018).…”

“…This would be analogous to what has been reported for the nucleus and other cytoplasmic organelles (Cremer et al, 2022;Etienne-Manneville, 2018). The Golgi ribbon, by virtue of its localization adjacent to the nucleus, may be embedded within the IF meshwork that forms a cage around the nucleus (Cremer et al, 2022;Etienne-Manneville, 2018). This would certainly be consistent with our imaging data.…”

“…Cytoplasmic vimentin IFs also contribute to the nuclear integrity by forming a cage around the nucleus that is mechanically protective (Patteson et al, 2019). A recent study has revealed that vimentin IFs can also associate with the endoplasmic reticulum and help maintain its morphological organization, as well as concentrate endolysosomes in the perinuclear area (Cremer et al, 2022). Vimentin cages can form around aggresomes to control protein degradation (Morrow and Moore, 2020; Morrow et al, 2020), lipid droplets (Franke et al, 1987), melanophores (Chang et al, 2009) and vimentin IFs also contribute to mitochondrial position and shape (Schwarz and Leube, 2016).…”

Models of vimentin organization under actin-driven transport

“…In addition, we found that scenario T3F, irreversible trapping with spatially dependent trapping, is unambiguously the best scenario out of the scenarios considered. The spatial profile of the trapping rate, particularly where it increases towards the cell center, is consistent with existing studies showing vimentin interaction with organelles, including the nucleus [54][55][56][57][58]. Furthermore, recalling that α(r) in this case is a net trapping rate, the negative values of α(r) towards the cell edge suggest that vimentin trapping is reduced at the cell periphery, possibly indicating a lower number of attachment sites for trapping [Fig.…”

“…Again considering all scenarios, the poor ranking of the constant-velocity and quantity-dependent velocity assumptions relative to the spatially dependent assumptions T3E and T3F is consistent with the biological observations of spatially dependent retrograde flow of actin [19] and the underlying compartmentalization of cell organelles interacting with vimentin [54][55][56][57][58], respectively. Because both scenarios are biologically plausible, we examine them in more detail.…”