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J Exp Med. 2019 Apr 1;216(4):807-830. doi: 10.1084/jem.20171438. Epub 2019 Feb 28.

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

Author information

1
Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.
2
Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany.
3
Department of Pathology, Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands.
4
Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany.
5
Department of Molecular Genetics, Cardiovascular Research Institute, Maastricht University, Maastricht, Netherlands.
6
Amsterdam Cardiovascular Sciences, Department of Medical Biochemistry, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
7
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
8
Biomedical Center, Metabolic Biochemistry, Ludwig Maximilians University of Munich, Munich, Germany.
9
Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany bernd.schroeder@tu-dresden.de.

Abstract

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.

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