Epsin-mediated degradation of IP3R1 fuels atherosclerosis
Open Access
- 7 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-16
- https://doi.org/10.1038/s41467-020-17848-4
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. Endothelial cell (EC) dysfunction and inflammation contribute to plaque destabilization in atherosclerosis, increasing the risk of thrombotic events. Here, the authors show that epsin promotes EC inflammation via a mechanism involving IP3R1 degradation, and that deletion of epsin in the endothelium prevents EC dysfunctoin and atherosclerosis in mice.Funding Information
- American Heart Association (12SDG8760002, 17SDG33630161, 17SDG33410868, Established Investigator Award)
- Oklahoma Center for the Advancement of Science and Technology (AR11-043, HR14-056)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01HL093242, R01HL118676, R01HL130845, R01HL133216, R01HL137229)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
This publication has 79 references indexed in Scilit:
- Endocytic Adaptor Protein Epsin Is Elevated in Prostate Cancer and Required for Cancer ProgressionISRN Oncology, 2013
- RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and DegradationOnline Journal of Public Health Informatics, 2011
- Role of Inositol 1,4,5-Trishosphate Receptors in Pathogenesis of Huntington’s Disease and Spinocerebellar AtaxiasNeurochemical Research, 2011
- Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at endocytic sites of apical canaliculiProceedings of the National Academy of Sciences of the United States of America, 2010
- Endoplasmic reticulum stress and atherosclerosisNature Medicine, 2010
- When worlds collide: IP3 receptors and the ERAD pathwayCell Calcium, 2009
- Substrate-specific mediators of ER associated degradation (ERAD)Current Opinion in Cell Biology, 2009
- Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in miceProceedings of the National Academy of Sciences of the United States of America, 2009
- Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependentThe Journal of Experimental Medicine, 2006
- Empirical Statistical Model To Estimate the Accuracy of Peptide Identifications Made by MS/MS and Database SearchAnalytical Chemistry, 2002