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

Shengkai Zuo1, Bei Wang1, Jiao Liu1

  • 1Tianjin 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.

The EMBO Journal
|July 5, 2021
PubMed

Insights

Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) degrades collagen mRNA in the endoplasmic reticulum, reducing organ fibrosis. This discovery offers a new therapeutic target for fibrotic diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Organ fibrosis is characterized by excessive extracellular matrix deposition, primarily collagen.
  • The molecular mechanisms controlling fibrotic protein synthesis remain largely unknown.

Purpose of the Study:

  • To investigate the role of chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) in regulating collagen biosynthesis and organ fibrosis.
  • To identify potential therapeutic targets for fibrotic diseases.

Main Methods:

  • Investigated CRTH2 trafficking to the endoplasmic reticulum (ER) membrane in fibroblasts.
  • Examined the interaction between CRTH2, La ribonucleoprotein domain family member 6 (LARP6), and collagen mRNA.
  • Assessed the effects of CRTH2 deficiency, LARP6 depletion, CRTH2 N-terminal peptide, and bumetanide on collagen production and organ fibrosis in mouse models.

Main Results:

  • ER-anchored CRTH2 binds LARP6, promoting collagen mRNA degradation in fibroblasts.
  • CRTH2 deficiency increased collagen biosynthesis and exacerbated organ fibrosis in mice.
  • LARP6 depletion rescued fibrosis in CRTH2-deficient mice.
  • CRTH2 N-terminal peptide and bumetanide suppressed collagen production and alleviated pulmonary fibrosis.

Conclusions:

  • CRTH2 exhibits an anti-fibrotic function by interacting with LARP6 in the ER membrane, leading to collagen mRNA degradation.
  • This CRTH2-LARP6 interaction represents a novel therapeutic strategy for treating fibrotic diseases.
Keywords:
CRTH2LARP6collagen synthesisorgan fibrosis

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