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Epsin-mediated degradation of IP3R1 fuels atherosclerosis

Author

Listed:
  • Yunzhou Dong

    (Harvard Medical School)

  • Yang Lee

    (Harvard Medical School)

  • Kui Cui

    (Harvard Medical School)

  • Ming He

    (University of California, San Diego)

  • Beibei Wang

    (Harvard Medical School)

  • Sudarshan Bhattacharjee

    (Harvard Medical School)

  • Bo Zhu

    (Harvard Medical School)

  • Tadayuki Yago

    (Oklahoma Medical Research Foundation)

  • Kun Zhang

    (Harvard Medical School)

  • Lin Deng

    (Harvard Medical School)

  • Kunfu Ouyang

    (University of California, San Diego)

  • Aiyun Wen

    (Harvard Medical School)

  • Douglas B. Cowan

    (Harvard Medical School
    Harvard Medical School)

  • Kai Song

    (Harvard Medical School)

  • Lili Yu

    (Harvard Medical School)

  • Megan L. Brophy

    (Harvard Medical School)

  • Xiaolei Liu

    (Feinberg Cardiovascular Research Institute, Feinberg School of Medicine)

  • Jill Wylie-Sears

    (Harvard Medical School)

  • Hao Wu

    (Harvard Medical School)

  • Scott Wong

    (Harvard Medical School)

  • Guanglin Cui

    (Harvard T.H. Chan School of Public Health)

  • Yusuke Kawashima

    (University of Oklahoma Health Sciences Center
    Kitasato University School of Science)

  • Hiroyuki Matsumoto

    (University of Oklahoma Health Sciences Center)

  • Yoshio Kodera

    (Kitasato University School of Science)

  • Richard J. H. Wojcikiewicz

    (SUNY Upstate Medical University)

  • Sanjay Srivastava

    (University of Louisville School of Medicine)

  • Joyce Bischoff

    (Harvard Medical School)

  • Da-Zhi Wang

    (Harvard Medical School)

  • Klaus Ley

    (La Jolla Institute for Allergy and Immunology)

  • Hong Chen

    (Harvard Medical School)

Abstract

The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.

Suggested Citation

  • Yunzhou Dong & Yang Lee & Kui Cui & Ming He & Beibei Wang & Sudarshan Bhattacharjee & Bo Zhu & Tadayuki Yago & Kun Zhang & Lin Deng & Kunfu Ouyang & Aiyun Wen & Douglas B. Cowan & Kai Song & Lili Yu &, 2020. "Epsin-mediated degradation of IP3R1 fuels atherosclerosis," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17848-4
    DOI: 10.1038/s41467-020-17848-4
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