Dataset Information

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

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ER-anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6.

Zuo Shengkai S Wang Bei B Liu Jiao J Kong Deping D Cui Hui H Jia Yaonan Y Wang Chenyao C Xu Xin X Chen Guilin G Wang Yuanyang Y Yang Linlin L Zhang Kai K Ai Ding D Du Jie J Shen Yujun Y Yu Ying Y

The EMBO journal 20210705 16

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 L ...[more]

PMID: 34223653

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Project description:Dupuytren's disease (DD) is a classic example of pathological fibrosis which results in a debilitating disorder affecting a large sector of the human population. It is characterized by excessive local proliferation of fibroblasts and over-production of collagen and other components of the extracellular matrix (ECM) in the palmar fascia. The fibrosis progressively results in contracture of elements between the palmar fascia and skin causing flexion deformity or clawing of the fingers and a severe reduction in hand function. While much is known about the pathogenesis and surgical treatment of DD, little is known about the factors that cause its onset and progression, despite many years of research. Gene expression patterns in DD patients now offers the potential to identify genes that direct the pathogenesis of DD. In this study, we used primary cultures of fibroblasts derived from excisional biopsies of fibrotic tissue from DD patients to compare the gene expression profiles on a genome-wide basis with normal control fibroblasts. Our investigations have identified genes that may be involved with DD pathogenesis including some which are directly relevant to fibrosis. In particular, these include significantly reduced expression levels of three matrix metallopeptidases (MMP1, MMP3, MMP16), follistatin, and STAT1, and significantly increased expression levels of fibroblast growth factors (FGF9, FGF11), a number of collagen genes and other ECM genes in DD patient samples. Many of these gene products are known to be involved in fibrosis, tumour formation and in the normal processes of tissue remodelling. In addition, alternative splicing was identified in some DD-associated genes. These highly sensitive genomic investigations provide new insight into the molecular mechanisms that may underpin the development and progression of DD. Four exon arrays of DD primary fibroblasts derived from fibrotic tissue were compared to fibroblasts derived from skin punch biopsies from individuals who did not show DD symptoms.

Dataset Information

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

Publications

ER-anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6.

Similar Datasets

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