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ER‐anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6
Authors:Shengkai Zuo  Bei Wang  Jiao Liu  Deping Kong  Hui Cui  Yaonan Jia  Chenyao Wang  Xin Xu  Guilin Chen  Yuanyang Wang  Linlin Yang  Kai Zhang  Ding Ai  Jie Du  Yujun Shen  Ying Yu
Abstract: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.
Keywords:collagen synthesis  CRTH2  LARP6  organ fibrosis
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