Jiu Yaming, Peränen Johan, Schaible Niccole, Cheng Fang, Eriksson John E, Krishnan Ramaswamy, Lappalainen Pekka
Institute of Biotechnology, P.O. Box 56, University of Helsinki, Helsinki 00014, Finland
Faculty of Medicine, P.O. Box 63, University of Helsinki, Helsinki 00014, Finland.
J Cell Sci. 2017 Mar 1;130(5):892-902. doi: 10.1242/jcs.196881. Epub 2017 Jan 17.
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 Geeves et al., 2015). 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.
肌动蛋白和中间丝细胞骨架参与众多细胞过程，包括形态发生、胞质分裂和迁移。这两种细胞骨架系统相互关联，但其相互作用的潜在机制仍未完全明确。在此，我们发现波形蛋白失活会导致肌动蛋白应力纤维组装增加和收缩性增强，进而使肌球蛋白轻链磷酸化水平升高以及原肌球蛋白-4.2稳定（见Geeves等人，2015年）。波形蛋白基因敲除的表型可通过野生型波形蛋白的重新表达得到挽救，但不能通过非丝状的“单位长度形式”波形蛋白挽救，这表明完整的波形蛋白中间丝对于促进对肌动蛋白细胞骨架的影响是必需的。最后，我们提供证据表明波形蛋白对应力纤维的影响是通过其鸟嘌呤核苷酸交换因子GEF-H1（也称为ARHGEF2）激活RhoA介导的。波形蛋白缺失会诱导微管相关的GEF-H1在Ser886位点磷酸化，从而促进RhoA活性和肌动蛋白应力纤维组装。综上所述，这些数据揭示了中间丝调节收缩性肌动球蛋白束的一种新机制，并且可能解释了为什么波形蛋白表达水平升高与癌细胞迁移和侵袭增加相关。
