Epsin-mediated degradation of IP3R1 fuels atherosclerosis.
Adaptor Proteins, Vesicular Transport
/ chemistry
Animals
Aorta
/ metabolism
Atherosclerosis
/ metabolism
Calcium
/ metabolism
Cholesterol
/ metabolism
Endothelial Cells
/ metabolism
Female
Gene Deletion
HEK293 Cells
Homeostasis
Humans
Inflammation
/ pathology
Inositol 1,4,5-Trisphosphate Receptors
/ metabolism
Male
Mice, Knockout
Protein Binding
Protein Domains
Proteolysis
Ubiquitination
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 08 2020
07 08 2020
Historique:
received:
26
08
2019
accepted:
15
07
2020
entrez:
10
8
2020
pubmed:
10
8
2020
medline:
10
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32770009
doi: 10.1038/s41467-020-17848-4
pii: 10.1038/s41467-020-17848-4
pmc: PMC7414107
doi:
Substances chimiques
Adaptor Proteins, Vesicular Transport
0
Inositol 1,4,5-Trisphosphate Receptors
0
epsin
0
Cholesterol
97C5T2UQ7J
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3984Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL133216
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146134
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL093242
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL145241
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL158097
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL134633
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141858
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141853
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137229
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL118676
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130845
Pays : United States
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