TY  - JOUR
AU  - Mentrup, Torben
AU  - Theodorou, Kosta
AU  - Cabrera-Cabrera, Florencia
AU  - Helbig, Andreas O
AU  - Happ, Kathrin
AU  - Gijbels, Marion
AU  - Gradtke, Ann-Christine
AU  - Rabe, Björn
AU  - Fukumori, Akio
AU  - Steiner, Harald
AU  - Tholey, Andreas
AU  - Fluhrer, Regina
AU  - Donners, Marjo
AU  - Schröder, Bernd
TI  - Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
JO  - Journal of experimental medicine
VL  - 216
IS  - 4
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DZNE-2020-06933
SP  - 807-830
PY  - 2019
AB  - 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.
KW  - ADAM10 Protein: metabolism
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Animals
KW  - Aspartic Acid Endopeptidases: antagonists & inhibitors
KW  - Aspartic Acid Endopeptidases: genetics
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Atherosclerosis: metabolism
KW  - Dipeptides: pharmacology
KW  - Endothelial Cells: metabolism
KW  - HEK293 Cells
KW  - HeLa Cells
KW  - Humans
KW  - Membrane Proteins: genetics
KW  - Membrane Proteins: metabolism
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Proteolysis
KW  - Scavenger Receptors, Class E: genetics
KW  - Scavenger Receptors, Class E: metabolism
KW  - Transfection
LB  - PUB:(DE-HGF)16
C6  - pmid:30819724
C2  - pmc:PMC6446863
DO  - DOI:10.1084/jem.20171438
UR  - https://pub.dzne.de/record/140611
ER  -