Targeting endoplasmic reticulum-anchored CRTH2 binding to LARP6 ameliorates organ fibrosis

ABSTRACT: Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms of the regulation of fibrotic protein biosynthesis are unclear. Here, we found that chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a cell membrane receptor for prostaglandin (PG) D2, is trafficked to the endoplasmic reticulum (ER) membrane in fibroblasts through Caveolin-1. CRTH2 anchored in the ER with bound collagen mRNA recognition motif (RRM) of La ribonucleoprotein domain family member 6 (LARP6) and promoted the degradation of collagen mRNA in fibroblasts. CRTH2 deficiency increased collagen biosynthesis in fibroblasts and exacerbated injury-induced organ fibrosis in mice, which was rescued by LARP6 depletion. Administration of CRTH2 N-terminal peptide reduced collagen production in fibroblasts by binding to LARP6. Similar to CRTH2, Bumetanide structurally bound to the LARP6 RRM domain, suppressed collagen biosynthesis in fibroblasts and alleviated bleomycin-triggered pulmonary fibrosis in mice. The findings reveal a novel anti-fibrotic function of CRTH2 in the ER membrane via interaction with LARP6, which may represent a therapeutic target for fibrotic diseases.

ORGANISM(S): Mus Sp.

SUBMITTER: Yujun Shen  

PROVIDER: PXD025610 | iProX | Sun Apr 25 00:00:00 BST 2021

REPOSITORIES: iProX