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Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
- Source :
- Journal of Experimental Medicine, 216(4), 807-830. Rockefeller University Press, Journal of experimental medicine 216(4), 807-830 (2019). doi:10.1084/jem.20171438, Journal of experimental medicine, 216(4), 807-830. Rockefeller University Press, The Journal of Experimental Medicine
- Publication Year :
- 2019
-
Abstract
- The intramembrane proteases SPPL2a/b control pro-atherogenic signaling of membrane-bound proteolytic fragments derived from the oxLDL receptor LOX-1. In mice deficient for these proteases, plaque development and fibrosis is enhanced. This highlights SPPL2a/b as crucial players of a novel athero-protective mechanism, which is conserved in humans.<br />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.<br />Graphical Abstract
- Subjects :
- 0301 basic medicine
medicine.medical_treatment
NF-KAPPA-B
TISSUE GROWTH-FACTOR
NUCLEAR TRANSLOCATION
030204 cardiovascular system & hematology
PROTEASE SPPL2A
ADAM10 Protein
Mice
0302 clinical medicine
metabolism [Scavenger Receptors, Class E]
Aspartic Acid Endopeptidases
Immunology and Allergy
metabolism [Atherosclerosis]
Receptor
Research Articles
OXIDIZED LDL RECEPTOR-1
Mice, Knockout
integumentary system
Kinase
Chemistry
Dipeptides
OX-LDL
antagonists & inhibitors [Aspartic Acid Endopeptidases]
metabolism [Aspartic Acid Endopeptidases]
Scavenger Receptors, Class E
Cell biology
Transmembrane domain
genetics [Membrane Proteins]
Ectodomain
metabolism [ADAM10 Protein]
lipids (amino acids, peptides, and proteins)
pharmacology [Dipeptides]
Signal peptide
Proteases
Immunology
LOW-DENSITY-LIPOPROTEIN
Transfection
PEPTIDASE-LIKE 2A
DENDRITIC CELLS
Article
03 medical and health sciences
metabolism [Endothelial Cells]
medicine
Animals
Humans
genetics [Scavenger Receptors, Class E]
ddc:610
PROMOTES ATHEROSCLEROSIS
Growth factor
Endothelial Cells
Membrane Proteins
Atherosclerosis
metabolism [Amyloid Precursor Protein Secretases]
CTGF
Mice, Inbred C57BL
030104 developmental biology
HEK293 Cells
genetics [Aspartic Acid Endopeptidases]
Proteolysis
Amyloid Precursor Protein Secretases
metabolism [Membrane Proteins]
HeLa Cells
Subjects
Details
- Language :
- English
- ISSN :
- 00221007
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine, 216(4), 807-830. Rockefeller University Press, Journal of experimental medicine 216(4), 807-830 (2019). doi:10.1084/jem.20171438, Journal of experimental medicine, 216(4), 807-830. Rockefeller University Press, The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....9ffa6a4d6e22e67e518e3fac901144fe