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

Torben Mentrup, Kosta Theodorou, Florencia Cabrera-Cabrera, Andreas O. Hethig, Kathrin Happ, Marion Gijbels, Ann-Christine Gradtke, Bjoern Rabe, Akio Fukumori, Harald Steiner, Andreas Tholey, Regina Fluhrer, Marjo Donners, Bernd Schroeder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)807-830
Number of pages24
JournalJournal of Experimental Medicine
Volume216
Issue number4
DOIs
Publication statusPublished - Apr 2019

Keywords

  • LOW-DENSITY-LIPOPROTEIN
  • NF-KAPPA-B
  • PEPTIDASE-LIKE 2A
  • OXIDIZED LDL RECEPTOR-1
  • TISSUE GROWTH-FACTOR
  • PROTEASE SPPL2A
  • DENDRITIC CELLS
  • OX-LDL
  • PROMOTES ATHEROSCLEROSIS
  • NUCLEAR TRANSLOCATION

Cite this

Mentrup, T., Theodorou, K., Cabrera-Cabrera, F., Hethig, A. O., Happ, K., Gijbels, M., Gradtke, A-C., Rabe, B., Fukumori, A., Steiner, H., Tholey, A., Fluhrer, R., Donners, M., & Schroeder, B. (2019). Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. Journal of Experimental Medicine, 216(4), 807-830. https://doi.org/10.1084/jem.20171438