Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis

• DOI: 10.1084/jem.20171438
• Publication Date: 2019-02-28T19:26:26Z
• Authors: Torben Mentrup; Kosta Theodorou; Florencia Cabrera...; Andreas O. Helbig; Kathrin Happ; Marion Gijbels; Ann-Christine Gra...; Björn Rabe; Akio Fukumori; Harald Steiner; Andreas Tholey; Regina Fluhrer; Marjo Donners; Bernd Schröder
• Keywords: NF-KAPPA-B; TISSUE GROWTH-FACTOR; LOW-DENSITY-LIPOPROTEIN; NUCLEAR TRANSLOCATION; PEPTIDASE-LIKE 2A; PROTEASE SPPL2A; Transfection; DENDRITIC CELLS; ADAM10 Protein; Mice; 03 medical and health sciences; metabolism [Scavenger Receptors, Class E]; metabolism [Endothelial Cells]; genetics [Scavenger Receptors, Class E]; Animals; Aspartic Acid Endopeptidases; Humans; metabolism [Atherosclerosis]; ddc:610; OXIDIZED LDL RECEPTOR-1; Research Articles; PROMOTES ATHEROSCLEROSIS; Mice, Knockout; ddc:610; 0303 health sciences; Endothelial Cells; Membrane Proteins; OX-LDL; Dipeptides; antagonists & inhibitors [Aspartic Acid Endopeptidases]; metabolism [Aspartic Acid Endopeptidases]; Atherosclerosis; Scavenger Receptors, Class E; metabolism [Amyloid Precursor Protein Secretases]; Mice, Inbred C57BL; genetics [Membrane Proteins]; HEK293 Cells; genetics [Aspartic Acid Endopeptidases]; Proteolysis; metabolism [ADAM10 Protein]; Amyloid Precursor Protein Secretases; pharmacology [Dipeptides]; metabolism [Membrane Proteins]; HeLa Cells

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.