Epsin-mediated degradation of IP3R1 fuels atherosclerosis

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, Megan L. Brophy, Xiaolei Liu, Jill Wylie-Sears, Hao Wu, Scott WongGuanglin Cui, Yusuke Kawashima, Hiroyuki Matsumoto, Yoshio Kodera, Richard J.H. Wojcikiewicz, Sanjay Srivastava, Joyce Bischoff, Da Zhi Wang, Klaus Ley, Hong Chen*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Article number3984
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Epsin-mediated degradation of IP3R1 fuels atherosclerosis'. Together they form a unique fingerprint.

  • Cite this

    Dong, Y., Lee, Y., Cui, K., He, M., Wang, B., Bhattacharjee, S., Zhu, B., Yago, T., Zhang, K., Deng, L., Ouyang, K., Wen, A., Cowan, D. B., Song, K., Yu, L., Brophy, M. L., Liu, X., Wylie-Sears, J., Wu, H., ... Chen, H. (2020). Epsin-mediated degradation of IP3R1 fuels atherosclerosis. Nature communications, 11(1), [3984]. https://doi.org/10.1038/s41467-020-17848-4