Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
ADAM10 Protein
/ metabolism
Amyloid Precursor Protein Secretases
/ metabolism
Animals
Aspartic Acid Endopeptidases
/ antagonists & inhibitors
Atherosclerosis
/ metabolism
Dipeptides
/ pharmacology
Endothelial Cells
/ metabolism
HEK293 Cells
HeLa Cells
Humans
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Proteolysis
Scavenger Receptors, Class E
/ genetics
Transfection
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 04 2019
01 04 2019
Historique:
received:
09
08
2017
revised:
21
08
2018
accepted:
17
10
2018
pubmed:
2
3
2019
medline:
6
5
2020
entrez:
2
3
2019
Statut:
ppublish
Résumé
The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake of oxidized LDL and inducing pro-atherogenic signaling. However, little is known about modulators of LOX-1-mediated responses. Here, we show that the function of LOX-1 is controlled proteolytically. Ectodomain shedding by the metalloprotease ADAM10 and lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which we identified as novel substrates of the intramembrane proteases signal peptide peptidase-like 2a and b (SPPL2a/b). SPPL2a/b control cellular LOX-1 NTF levels which, following self-association via their transmembrane domain, can activate MAP kinases in a ligand-independent manner. This leads to an up-regulation of several pro-atherogenic and pro-fibrotic targets including ICAM-1 and the connective tissue growth factor CTGF. Consequently, SPPL2a/b-deficient mice, which accumulate LOX-1 NTFs, develop larger and more advanced atherosclerotic plaques than controls. This identifies intramembrane proteolysis by SPPL2a/b as a novel atheroprotective mechanism via negative regulation of LOX-1 signaling.
Identifiants
pubmed: 30819724
pii: jem.20171438
doi: 10.1084/jem.20171438
pmc: PMC6446863
doi:
Substances chimiques
1, 3-di-(N-carboxybenzoyl-leucyl-leucyl)amino acetone
0
Dipeptides
0
Membrane Proteins
0
OLR1 protein, human
0
Olr1 protein, mouse
0
Scavenger Receptors, Class E
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
SPPL2a protein, human
EC 3.4.23.-
SPPL2a protein, mouse
EC 3.4.23.-
SPPL2b protein, human
EC 3.4.23.-
SPPL2b protein, mouse
EC 3.4.23.-
ADAM10 Protein
EC 3.4.24.81
ADAM10 protein, human
EC 3.4.24.81
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
807-830Informations de copyright
© 2019 Mentrup et al.
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