Vimentin intermediate filaments control actin stress fiber assembly through GEF-H1 and RhoA.
Vimentin intermediate filaments control actin stress fiber assembly through GEF-H1 and RhoA.
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DOI：
10.1242/jcs.196881
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发表时间：
2017-03-01
影响因子：
4
通讯作者：
Lappalainen P
中科院分区：
文献类型：
--
作者：
Jiu Y;Peränen J;Schaible N;Cheng F;Eriksson JE;Krishnan R;Lappalainen P
肌动蛋白和中间丝细胞骨架参与许多细胞过程，包括形态发生、胞质分裂和迁移。这两个细胞骨架系统相互关联，但这种相互作用的潜在机制尚不完全清楚。在这里，我们表明，波形蛋白的失活导致肌动蛋白应力纤维组装和收缩能力增加，从而提高肌球蛋白轻链磷酸化和原肌球蛋白-4.2的稳定性(参见)。野生型Vimentin的重新表达可以挽救Vimentin敲除表型，但非丝状“单位长度形式”Vimentin不能挽救Vimentin敲除表型，这表明需要完整的Vimentin中间丝才能促进对肌动蛋白细胞骨架的影响。最后，我们提供的证据表明，波形蛋白对应激纤维的影响是通过其鸟核苷酸交换因子Gen-H1(也称为ARHGEF2)激活RhoA来实现的。波形蛋白缺失可诱导Ser886上微管相关的gef-h1的磷酸化，从而促进RhoA活性和肌动蛋白应激纤维组装。综上所述，这些数据揭示了中间丝调节收缩肌球蛋白束的新机制，并可能解释为什么波形蛋白表达水平升高与癌细胞的迁移和侵袭增加相关。摘要：波形蛋白中间丝通过下调其鸟嘌呤核苷酸交换因子gef-h1来控制RhoA的活性，从而控制应激纤维的组装和收缩。
The actin and intermediate filament cytoskeletons contribute to numerous cellular processes, including morphogenesis, cytokinesis and migration. These two cytoskeletal systems associate with each other, but the underlying mechanisms of this interaction are incompletely understood. Here, we show that inactivation of vimentin leads to increased actin stress fiber assembly and contractility, and consequent elevation of myosin light chain phosphorylation and stabilization of tropomyosin-4.2 (see). The vimentin-knockout phenotypes can be rescued by re-expression of wild-type vimentin, but not by the non-filamentous ‘unit length form’ vimentin, demonstrating that intact vimentin intermediate filaments are required to facilitate the effects on the actin cytoskeleton. Finally, we provide evidence that the effects of vimentin on stress fibers are mediated by activation of RhoA through its guanine nucleotide exchange factor GEF-H1 (also known as ARHGEF2). Vimentin depletion induces phosphorylation of the microtubule-associated GEF-H1 on Ser886, and thereby promotes RhoA activity and actin stress fiber assembly. Taken together, these data reveal a new mechanism by which intermediate filaments regulate contractile actomyosin bundles, and may explain why elevated vimentin expression levels correlate with increased migration and invasion of cancer cells. Summary: Vimentin intermediate filaments control the activity of RhoA, and consequent stress fiber assembly and contractility by downregulating its guanine nucleotide exchange factor GEF-H1.