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

The Journal of Experimental Medicine
Torben MentrupBernd Schröder

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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Citations

Aug 17, 2019·Journal of Cell Science·Nathalie KühnleMarius K Lemberg
Oct 4, 2019·European Journal of Immunology·Kazuya ToneGordon D Brown
Feb 14, 2020·Cellular and Molecular Life Sciences : CMLS·Torben MentrupBernd Schröder
Oct 5, 2019·Aging·Torben Mentrup, Bernd Schröder
Mar 7, 2020·Frontiers in Immunology·Marion DrouinElise Chiffoleau
Feb 16, 2020·Communications Biology·Thomas KupkeBritta Brügger
Jul 25, 2019·Antioxidants·Ajoe John KattoorJawahar L Mehta
Jan 1, 2021·Frontiers in Cardiovascular Medicine·Alkmini A Papadopoulou, Regina Fluhrer
Jan 7, 2021·Cancer Gene Therapy·M MurdoccaF Sangiuolo
Feb 9, 2021·Frontiers in Cardiovascular Medicine·Torben MentrupBernd Schröder

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Methods Mentioned

BETA
glycosylation
PMA
I-CLIPs
flow cytometry
coimmunoprecipitation
immunoprecipitation
PCR
FCS
transfection
Protein Assay

Software Mentioned

FlowJo
Proteome Discoverer
FACSDiva
ImageJ
GraphPad Prism
Tree Star
Adobe Photoshop
Ensembl
Olympus Fluoview

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