TY - JOUR
T1 - Epsin-mediated degradation of IP3R1 fuels atherosclerosis
AU - Dong, Yunzhou
AU - Lee, Yang
AU - Cui, Kui
AU - He, Ming
AU - Wang, Beibei
AU - Bhattacharjee, Sudarshan
AU - Zhu, Bo
AU - Yago, Tadayuki
AU - Zhang, Kun
AU - Deng, Lin
AU - Ouyang, Kunfu
AU - Wen, Aiyun
AU - Cowan, Douglas B.
AU - Song, Kai
AU - Yu, Lili
AU - Brophy, Megan L.
AU - Liu, Xiaolei
AU - Wylie-Sears, Jill
AU - Wu, Hao
AU - Wong, Scott
AU - Cui, Guanglin
AU - Kawashima, Yusuke
AU - Matsumoto, Hiroyuki
AU - Kodera, Yoshio
AU - Wojcikiewicz, Richard J.H.
AU - Srivastava, Sanjay
AU - Bischoff, Joyce
AU - Wang, Da Zhi
AU - Ley, Klaus
AU - Chen, Hong
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-17848-4
DO - 10.1038/s41467-020-17848-4
M3 - Article
C2 - 32770009
AN - SCOPUS:85089177853
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3984
ER -