Epsin-mediated degradation of IP3R1 fuels atherosclerosis.

Nat Commun. 2020 Aug 07;11(1):3984

Yunzhou Dong ¹ , Yang Lee ¹ , Kui Cui ¹ , Ming He ² , Beibei Wang ¹ ,

Yunzhou Dong ¹ , Yang Lee ¹ , Kui Cui ¹ , Ming He ² , Beibei Wang ¹ , Sudarshan Bhattacharjee ¹ , Bo Zhu ¹ , Tadayuki Yago ³ , Kun Zhang ¹ , Lin Deng ⁴ , Kunfu Ouyang ² , Aiyun Wen ¹ , Douglas B Cowan ⁵ , Kai Song ¹ , Lili Yu ¹ , Megan L Brophy ¹ , Xiaolei Liu ⁶ , Jill Wylie-Sears ¹ , Hao Wu ¹ , Scott Wong ¹ , Guanglin Cui ⁷ , Yusuke Kawashima ⁸ , Hiroyuki Matsumoto ⁹ , Yoshio Kodera ⁸ , Richard J H Wojcikiewicz ¹⁰ , Sanjay Srivastava ¹¹ , Joyce Bischoff ¹ , Da-Zhi Wang ⁵ , Klaus Ley ¹² , Hong Chen ¹³

+ et al

Author information

¹ Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
² Department of Medicine, University of California, San Diego, San Diego, CA, 92093, USA.
³ Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
⁴ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
⁵ Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁶ Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Chicago, IL, 60611, USA.
⁷ Department of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
⁸ Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.
⁹ Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
¹⁰ Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
¹¹ Department of Medicine, Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
¹² La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
¹³ Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. hong.chen@childrens.harvard.edu.

摘要

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.

原始数据

保存测序数据

Sample name	Organism	Experiment title	Sample type	Library instrument	Attributes
Sample name	Organism	Experiment title	Sample type	Library instrument