SM22α suppresses cytokine-induced inflammation and the transcription of NF-κB inducing kinase (Nik) by modulating SRF transcriptional activity in vascular smooth muscle cells.

Abstract

Vascular smooth muscle cell (VSMC) phenotypic modulation is characterized by the downregulation of SMC actin cytoskeleton proteins. Our published study shows that depletion of SM22α (aka SM22, Transgelin, an actin cytoskeleton binding protein) promotes inflammation in SMCs by activating NF-κB 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-κB signaling pathways under inflammatory condition. NF-κB inducing kinase (Nik, aka MAP3K14, activated by the LTβR) is a key upstream regulator of NF-κB signal pathways. Here, we show that SM22 overexpression suppresses the expression of NIK and its downstream NF-κB canonical and noncanonical signal pathways in a VSMC line treated with a LTβR 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-kB signal pathways as a modulator of SRF during vascular inflammation.

• Authors: Xiaohua Dai, Devi Thiagarajan, Jingye Fang, Jianbin Shen, Neeraja Priyanka Annam, Zhao Yang, Hong Jiang, Donghong Ju, Youming Xie, Kezhong Zhang, Yan Yuan Tseng, Zhe Yang, Arun K Rishi, Hui J Li, Maozhou Yang, Li Li
• Journal: PloS one (PLoS One) Vol. 12 Issue 12 Pg. e0190191 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 29284006 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Microfilament Proteins
• Muscle Proteins
• Tagln protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Line
• Cytokines (physiology)
• Inflammation (physiopathology)
• Mice
• Microfilament Proteins (genetics, physiology)
• Muscle Proteins (genetics, physiology)
• Muscle, Smooth, Vascular (cytology, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Transcription, Genetic
• NF-kappaB-Inducing Kinase