A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin-proteasome system, and causes posterior cataracts in transgenic mice

Abstract

Vimentin is the main intermediate filament (IF) protein of mesenchymal cells and tissues. Unlike other IF–/– mice, vimentin–/– mice provided no evidence of an involvement of vimentin in the development of a specific disease. Therefore, we generated two transgenic mouse lines, one with a (R113C) point mutation in the IF-consensus motif in coil1A and one with the complete deletion of coil 2B of the rod domain. In epidermal keratins and desmin, point mutations in these parts of the α-helical rod domain cause keratinopathies and desminopathies, respectively. Here, we demonstrate that substoichiometric amounts of vimentin carrying the R113C point mutation disrupted the endogenous vimentin network in all tissues examined but caused a disease phenotype only in the eye lens, leading to a posterior cataract that was paralleled by the formation of extensive protein aggregates in lens fibre cells. Unexpectedly, central, postmitotic fibres became depleted of aggregates, indicating that they were actively removed. In line with an increase in misfolded proteins, the amounts of Hsp70 and ubiquitylated vimentin were increased, and proteasome activity was raised. We demonstrate here for the first time that the expression of mutated vimentin induces a protein-stress response that contributes to disease pathology in mice, and hypothesise that vimentin mutations cause cataracts in humans.

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

“…5A), which suggests an absence of protein toxicity in this injury model. This finding contrasts that found in transgenic mice overexpressing mutated vimentin where misfolded vimentin is found to trigger the up-regulation of HSP-70 due to protein aggregation toxicity (33).…”

Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-β–Slug signaling

“…In relation to vimentin's role in maintaining lens homeostasis and integrity, vimentin mutations have also been linked with cataract formation (17,18). Furthermore, we have demonstrated previously that vimentin is required in inflammatory cell migration; vimentin-deficient lymphocytes have a reduced transmigration capability in vivo because of the downregulation of the adhesion molecule ICAM-1 and integrins on the cell surface (19).…”

Functions of the intermediate filament cytoskeleton in the eye lens

“…The R-to-C change in the LNDR motif of BFSP2 would actually cause disease if found in, for example, glial fibrillary acidic protein (GFAP) (110), and for this reason the motif is colored red in the schematic. In fact, an R113C mutation causes cataract in mice when introduced into vimentin (87). Clearly, it is the context of such a change that will determine whether this alone will abrogate filament function.…”

“…Although mice lacking vimentin do not have a published lens phenotype (85), overexpression of vimentin in the lens causes cataract (86). Recently, the introduction of an Arg-to-Cys mutation in the LNDR motif in helix 1A of vimentin produced a dominant negative mutant, and mice transgenic for this mutant developed cataract (87). Further, the first vimentin mutation (E151K) to cause cataract in humans has been identified (19).…”