Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Pharmacology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
EMBO J. 2021 Aug 16;40(16):e107403. doi: 10.15252/embj.2020107403. Epub 2021 Jul 5.
Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms regulating fibrotic protein biosynthesis are unclear. Here, we find that chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a plasma membrane receptor for prostaglandin D2, is trafficked to the endoplasmic reticulum (ER) membrane in fibroblasts in a caveolin-1-dependent manner. ER-anchored CRTH2 binds the collagen mRNA recognition motif of La ribonucleoprotein domain family member 6 (LARP6) and promotes the degradation of collagen mRNA in these cells. In line, CRTH2 deficiency increases collagen biosynthesis in fibroblasts and exacerbates injury-induced organ fibrosis in mice, which can be rescued by LARP6 depletion. Administration of CRTH2 N-terminal peptide reduces collagen production by binding to LARP6. Similar to CRTH2, bumetanide binds the LARP6 mRNA recognition motif, suppresses collagen biosynthesis, and alleviates bleomycin-triggered pulmonary fibrosis in vivo. These findings reveal a novel anti-fibrotic function of CRTH2 in the ER membrane via the interaction with LARP6, which may represent a therapeutic target for fibrotic diseases.
细胞外基质的过度沉积，主要是胶原蛋白，是器官纤维化的标志。调节纤维化蛋白生物合成的分子机制尚不清楚。在这里，我们发现，2 型辅助性 T 细胞表达的趋化因子受体同源物（CRTH2），即前列腺素 D2 的质膜受体，以依赖 caveolin-1 的方式被转运到成纤维细胞的内质网膜上。内质网锚定的 CRTH2 与 La 核糖核蛋白家族成员 6（LARP6）的胶原蛋白 mRNA 识别基序结合，并促进这些细胞中胶原蛋白 mRNA 的降解。与此一致，CRTH2 缺陷增加了成纤维细胞中胶原蛋白的生物合成，并加重了损伤诱导的小鼠器官纤维化，而 LARP6 耗竭可挽救这种情况。CRTH2 N 端肽通过与 LARP6 结合来减少胶原蛋白的产生。类似于 CRTH2，布美他尼结合 LARP6 的 mRNA 识别基序，抑制胶原蛋白生物合成，并减轻体内博来霉素引发的肺纤维化。这些发现揭示了 CRTH2 在 ER 膜中通过与 LARP6 相互作用的新型抗纤维化功能，这可能代表纤维化疾病的治疗靶点。
