%0 Journal Article
%A Mentrup, Torben
%A Theodorou, Kosta
%A Cabrera-Cabrera, Florencia
%A Helbig, Andreas O
%A Happ, Kathrin
%A Gijbels, Marion
%A Gradtke, Ann-Christine
%A Rabe, Björn
%A Fukumori, Akio
%A Steiner, Harald
%A Tholey, Andreas
%A Fluhrer, Regina
%A Donners, Marjo
%A Schröder, Bernd
%T Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
%J Journal of experimental medicine
%V 216
%N 4
%@ 0022-1007
%C New York, NY
%I Rockefeller Univ. Press
%M DZNE-2020-06933
%P 807-830
%D 2019
%X 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.
%K ADAM10 Protein: metabolism
%K Amyloid Precursor Protein Secretases: metabolism
%K Animals
%K Aspartic Acid Endopeptidases: antagonists & inhibitors
%K Aspartic Acid Endopeptidases: genetics
%K Aspartic Acid Endopeptidases: metabolism
%K Atherosclerosis: metabolism
%K Dipeptides: pharmacology
%K Endothelial Cells: metabolism
%K HEK293 Cells
%K HeLa Cells
%K Humans
%K Membrane Proteins: genetics
%K Membrane Proteins: metabolism
%K Mice
%K Mice, Inbred C57BL
%K Mice, Knockout
%K Proteolysis
%K Scavenger Receptors, Class E: genetics
%K Scavenger Receptors, Class E: metabolism
%K Transfection
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30819724
%2 pmc:PMC6446863
%R 10.1084/jem.20171438
%U https://pub.dzne.de/record/140611