莫辛
放射毒素
细胞生物学
埃兹林
细胞骨架
肌动蛋白细胞骨架
化学
生物
细胞
生物化学
作者
Serhan Karvar,Ephraim Ansa-Addo,Jo Suda,Shweta Singh,Lixin Zhu,Zihai Li,Don C. Rockey
出处
期刊:Hepatology
[Wiley]
日期:2019-12-20
卷期号:72 (3): 1073-1084
被引量:20
摘要
Background and Aims Moesin, an ezrin/radixin/moesin family member, is involved in the regulation of cell adhesion, polarity, and migration by cross‐linking between the actin cytoskeleton and plasma membrane. The primary effector cell in hepatic fibrosis is the hepatic stellate cell (HSC), which undergoes activation during liver injury leading to increased extracellular matrix production. Approach and Results Here, we have hypothesized that moesin plays a critical role in linking the HSC cytoskeleton to the fibrogenic cascade during HSC activation. Moesin phosphorylation was up‐regulated during HSC activation and fibrogenesis. Using moesin wild‐type (WT) and mutant constructs (phosphomimicking T558D and nonphosphorylatable T558A), we found that cellular motility and contraction were increased in moesin WT‐infected and T558D‐infected cells, paralleled by an increase in smooth muscle α‐actin and collagen 1 expression. In contrast, overexpression of nonphosphorylatable moesin and moesin knockout (KO) decreased cellular motility and contraction. Most importantly, moesin KO led to abrogation of liver fibrosis. The mechanism of moesin's effect was a reduction in myocardin‐related transcription factor‐A and serum‐response factor (SRF)–mediated changes in the actin cytoskeleton, which in turn modulated the expression of matrix genes. Conclusions Taken together, our findings suggest that the linkage between cytoskeletal dynamics and the correlated MRTF/SRF signaling pathway has a pivotal role in HSC activation and fibrogenesis.
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