ER-anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6
ER-anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6
复制标题
ER 锚定的 CRTH2 通过结合 LARP6 拮抗胶原蛋白生物合成和器官纤维化
DOI：
10.15252/embj.2020107403
复制
发表时间：
2021-07-05
期刊：
影响因子：
11.4
通讯作者：
Yu, Ying
中科院分区：
文献类型：
--
作者：
Zuo, Shengkai;Wang, Bei;Yu, Ying
细胞外基质（主要是胶原蛋白）的过度沉积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TH 2细胞上表达的化学引诱物受体同源分子（CRTH 2）是前列腺素D2的质膜受体，它以小窝蛋白-1依赖性的方式被运输到成纤维细胞的内质网（ER）膜。ER锚定的CRTH 2结合La核糖核蛋白结构域家族成员6（LARP 6）的胶原mRNA识别基序，并促进这些细胞中胶原mRNA的降解。与此一致，CRTH 2缺乏增加成纤维细胞中的胶原蛋白生物合成，并加剧小鼠中损伤诱导的器官纤维化，这可以通过LARP 6耗竭来挽救。施用CRTH 2 N-末端肽通过与LARP 6结合减少胶原蛋白产生。与CRTH 2类似，布美他尼结合LARP 6 mRNA识别基序，抑制胶原蛋白生物合成，并在体内消除博来霉素引发的肺纤维化。这些发现揭示了CRTH 2通过与LARP 6相互作用在ER膜中的新的抗纤维化功能，LARP 6可能代表纤维化疾病的治疗靶点。
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.