Serhan Karvar1, Ephraim A Ansa-Addo2, Jo Suda3, Shweta Singh4, Lixin Zhu5,6,7, Zihai Li2, Don C Rockey1. 1. Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC. 2. Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC. 3. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA. 4. Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC. 5. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 6. Department of Biochemistry, University at Buffalo, Buffalo, NY. 7. Department of Pediatrics, University at Buffalo, Buffalo, NY.
Abstract
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.
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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