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CRP2-MRTF 相互作用在肌成纤维细胞功能中的作用。

Role of CRP2-MRTF interaction in functions of myofibroblasts.

机构信息

Department of RNA Biology and Neuroscience, Osaka University Graduate School of Medicine.

Department of Ophthalmology, Yamaguchi University Graduate School of Medicine.

出版信息

Cell Struct Funct. 2023;48(1):83-98. doi: 10.1247/csf.23004.

DOI:10.1247/csf.23004
PMID:37164693
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10721955/
Abstract

Inflammatory response induces phenotypic modulation of fibroblasts into myofibroblasts. Although transforming growth factor-βs (TGF-βs) evoke such transition, the details of the mechanism are still unknown. Here, we report that a LIM domain protein, cysteine-and glycine-rich protein 2 (CSRP2 [CRP2]) plays a vital role in the functional expression profile in myofibroblasts and cancer-associated fibroblasts (CAFs). Knock-down of CRP2 severely inhibits the expression of smooth muscle cell (SMC) genes, cell motility, and CAF-mediated collective invasion of epidermoid carcinoma. We elucidate the following molecular bases: CRP2 directly binds to myocardin-related transcription factors (MRTF-A/B [MRTFs]) and serum response factor (SRF) and stabilizes the MRTF/SRF/CArG-box complex to activate SMC gene expression. Furthermore, a three-dimensional structural analysis of CRP2 identifies the amino acids required for the CRP2-MRTF-A interaction. Polar amino acids in the C-terminal half (serine-152, glutamate-154, serine-155, threonine-156, threonine-157, and threonine-159 in human CRP2) are responsible for direct binding to MRTF-A. On the other hand, hydrophobic amino acids outside the consensus sequence of the LIM domain (tryptophan-139, phenylalanine-144, leucine-153, and leucine-158 in human CRP2) play a role in stabilizing the unique structure of the LIM domain.Key words: CRP2, 3D structure, myocardin-related transcription factor, myofibroblast, cancer-associated fibroblasts.

摘要

炎症反应诱导成纤维细胞向肌成纤维细胞的表型调节。虽然转化生长因子-β（TGF-β）引发这种转变，但机制的细节仍不清楚。在这里，我们报告 LIM 结构域蛋白，半胱氨酸和甘氨酸丰富蛋白 2（CSRP2 [CRP2]）在肌成纤维细胞和癌症相关成纤维细胞（CAFs）的功能表达谱中发挥重要作用。CRP2 的敲低严重抑制平滑肌细胞（SMC）基因、细胞迁移和表皮癌细胞的 CAF 介导的集体侵袭的表达。我们阐明了以下分子基础：CRP2 直接结合肌球蛋白相关转录因子（MRTF-A/B [MRTFs]）和血清反应因子（SRF），并稳定 MRTF/SRF/CArG 盒复合物以激活 SMC 基因表达。此外，CRP2 的三维结构分析确定了 CRP2-MRTF-A 相互作用所需的氨基酸。CRP2 中 C 端半胱氨酸（人 CRP2 中的丝氨酸-152、谷氨酸-154、丝氨酸-155、苏氨酸-156、苏氨酸-157 和苏氨酸-159）负责与 MRTF-A 的直接结合。另一方面，LIM 结构域保守序列之外的疏水性氨基酸（人 CRP2 中的色氨酸-139、苯丙氨酸-144、亮氨酸-153 和亮氨酸-158）在稳定 LIM 结构域的独特结构中发挥作用。

关键词

CRP2、3D 结构、肌球蛋白相关转录因子、肌成纤维细胞、癌症相关成纤维细胞。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/351c/10721955/02b28d1cba53/csf_48_23004-f007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/351c/10721955/73eb9d8a866e/csf_48_23004-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/351c/10721955/ec491e8fa76d/csf_48_23004-f002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/351c/10721955/6ba1fdfdb710/csf_48_23004-f004.jpg
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