A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin-proteasome system, and causes posterior cataracts in transgenic mice
A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin-proteasome system, and causes posterior cataracts in transgenic mice
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DOI：
10.1242/jcs.030312
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发表时间：
2008-11-15
影响因子：
4
通讯作者：
Magin, Thomas M.
中科院分区：
文献类型：
--
作者：
Bornheim, Roland;Mueller, Martin;Magin, Thomas M.
波形蛋白是间充质细胞和组织的主要中间丝蛋白。与其他IF-/-小鼠不同，波形蛋白（-/-）小鼠没有提供波形蛋白参与特定疾病发展的证据。因此，我们产生了两个转基因小鼠品系，一个在coil 1A中的IF-共有基序中具有（R113 C）点突变，另一个具有杆结构域的coil 2B的完全缺失。在表皮角蛋白和结蛋白中，α-螺旋杆结构域的这些部分中的点突变分别引起角蛋白病和结蛋白病。在这里，我们证明，亚化学计量的波形蛋白携带的R113 C点突变破坏了内源性波形蛋白网络在所有组织检查，但只在眼睛透镜引起的疾病表型，导致后白内障，这是由广泛的蛋白质聚集体形成在透镜纤维细胞。出乎意料的是，中央，有丝分裂后的纤维成为耗尽的聚集体，表明它们被积极删除。与错误折叠蛋白的增加一致，Hsp 70和泛素化波形蛋白的量增加，蛋白酶体活性升高。我们在这里首次证明，突变的波形蛋白的表达诱导蛋白质应激反应，有助于小鼠的疾病病理，并假设波形蛋白突变导致人类白内障。
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 alpha-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.