Many IF disorders are caused by mutations in coil 1A of the rod domain. ![]() Based on the high degree of sequence conservation among vimentin and other IF proteins, such as desmins, we undertook a new approach to study the function of vimentin by expressing a mutated vimentin gene in mice. Most importantly, vimentin is one of the very few IF genes which so far has not been linked to a human disease ( Magin et al., 2004 Magin et al., 2007 Kim and Coulombe, 2007). The ubiquitin-proteasome system is responsible for the degradation of misfolded and short-lived proteins into peptide fragments ( Arndt et al., 2007).ĭespite extensive studies, solid information on specific functions of vimentin in different tissues and specific cell types in vivo is still limited. Whereas the majority of co-chaperones serve the refolding of proteins into the native state, several co-chaperones that link chaperones to the ubiquitin-proteasome system have recently been identified ( Arndt et al., 2007). Hsp70 chaperones are able to bind a large number of non-native proteins in an ATP-dependent manner and are regulated by co-chaperones. Most importantly, chaperones facilitate either the refolding of mutant proteins or their removal by the protein degradation machinery. Molecular chaperones assist the folding of nascent polypeptides, avoid the formation of protein aggregates and regulate the subcellular distribution of proteins to their correct localisation. In addition to the accumulation of misfolded protein – which is specific for the disease – the common denominators of such protein aggregates are the presence of ubiquitin, components of the proteasome complex and molecular chaperones, including Hsp70 and Hsp40. Although the corresponding pathomechanisms are not well understood, it is widely accepted that they result from a failure of different quality-control mechanisms for proteins. Protein aggregates that are typical for EBS, and resemble those found in other IF disorders and in many neurodegenerative diseases that are collectively referred to as protein-conformational disorders. ![]() 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. In line with an increase in misfolded proteins, the amounts of Hsp70 and ubiquitylated vimentin were increased, and proteasome activity was raised. Unexpectedly, central, postmitotic fibres became depleted of aggregates, indicating that they were actively removed. 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. In epidermal keratins and desmin, point mutations in these parts of the α-helical rod domain cause keratinopathies and desminopathies, respectively. 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. ![]() ![]() Unlike other IF –/– mice, vimentin –/– mice provided no evidence of an involvement of vimentin in the development of a specific disease. Vimentin is the main intermediate filament (IF) protein of mesenchymal cells and tissues.
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