SM22α suppresses cytokine- induced inflammation and the transcription of NF-κB inducing kinase (Nik) by modulating SRF transcriptional activity in vascular smooth muscle cells
SM22α suppresses cytokine- induced inflammation and the transcription of NF-κB inducing kinase (Nik) by modulating SRF transcriptional activity in vascular smooth muscle cells
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DOI：
10.1371/journal.pone.0190191
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发表时间：
2017-12-28
期刊：
影响因子：
3.7
通讯作者：
Li, Li
中科院分区：
文献类型：
--
作者：
Dai, Xiaohua;Thiagarajan, Devi;Li, Li
血管平滑肌细胞(VSMC)的表型改变以SMC肌动蛋白细胞骨架蛋白下调为特征。我们已发表的研究表明，SM22a(又名SM22，Transglin，一种肌动蛋白细胞骨架结合蛋白)的缺失通过激活培养的VSMC和血管损伤反应中的NF-kappa B信号通路来促进SMC的炎症。本研究的目的是探讨SM22在炎症条件下抑制核因子-kappaB信号通路的分子机制。核因子-kappa B诱导激酶(NIK，又名MAP3K14，由LTβR激活)是核因子-kappa B信号通路的上游调节因子。在这里，我们发现SM22的过表达抑制了经LTβR激动剂处理的VSMC中NIK及其下游的NF-kappa B正则和非正则信号通路的表达。SM22根据培养条件在转录水平和蛋白酶体介导的翻译后水平上调节VSMC中Nik的表达。通过定量聚合酶链式反应、染色质免疫沉淀和荧光素酶活性检测，我们发现Nik是血清反应因子(SRF)的转录靶标。虽然已知SM22在细胞质中表达，但我们发现SM22也在细胞核中表达，SM22与SRF相互作用，抑制Nik和典型的SRF调控基因包括c-fos和egr3的转录。此外，颈动脉损伤增加了Sm22(-/-)小鼠NIK的表达，这一作用可通过腺病毒转导的SM22部分缓解。这些发现首次揭示了SM22除在VSMCs胞浆外还在细胞核内表达，在血管炎症过程中作为SRF的调节物，调节Nik及其下游的促炎因子NF-kappaB信号通路的转录。
Vascular smooth muscle cell (VSMC) phenotypic modulation is characterized by the down-regulation of SMC actin cytoskeleton proteins. Our published study shows that depletion of SM22a (aka SM22, Transgelin, an actin cytoskeleton binding protein) promotes inflammation in SMCs by activating NF-kappa B signal pathways both in cultured VSMCs and in response to vascular injury. The goal of this study is to investigate the underlying molecular mechanisms whereby SM22 suppresses NF-kappa B signaling pathways under inflammatory condition. NF-kappa B inducing kinase (Nik, aka MAP3K14, activated by the LT beta R) is a key upstream regulator of NF-kappa B signal pathways. Here, we show that SM22 overexpression suppresses the expression of NIK and its downstream NF-kappa B canonical and noncanonical signal pathways in a VSMC line treated with a LT beta R agonist. SM22 regulates NIK expression at both transcriptional and the proteasome-mediated post-translational levels in VSMCs depending on the culture condition. By qPCR, chromatin immunoprecipitation and luciferase assays, we found that Nik is a transcription target of serum response factor (SRF). Although SM22 is known to be expressed in the cytoplasm, we found that SM22 is also expressed in the nucleus where SM22 interacts with SRF to inhibit the transcription of Nik and prototypical SRF regulated genes including c-fos and Egr3. Moreover, carotid injury increases NIK expression in Sm22(-/-) mice, which is partially relieved by adenovirally transduced SM22. These findings reveal for the first time that SM22 is expressed in the nucleus in addition to the cytoplasm of VSMCs to regulate the transcription of Nik and its downstream proinflammatory NF-kappa B signal pathways as a modulator of SRF during vascular inflammation.