Atherogenic LOX-1 Signaling is Controlled by SPPL2-mediated Intramembrane Proteolysis

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2019 Mar 2

PMID 30819724

Citations 19

Authors

Torben Mentrup

Kosta Theodorou

Florencia Cabrera-Cabrera

Andreas O Helbig

Kathrin Happ

Marion Gijbels

Ann-Christine Gradtke

Bjorn Rabe

Akio Fukumori

Harald Steiner

Andreas Tholey

Regina Fluhrer

Marjo Donners

Bernd Schroder

Affiliations

Soon will be listed here.

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.

Citing Articles

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