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 Wong, Guanglin Cui, Yusuke Kawashima, Hiroyuki Matsumoto, Yoshio Kodera, Richard J. H. Wojcikiewicz, Sanjay Srivastava, Joyce Bischoff, Da-Zhi Wang, Klaus Ley and Hong Chen ()
Additional contact information
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
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
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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17848-4

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