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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / metabolism
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Atherosclerosis / metabolism
  • Dipeptides / pharmacology
  • Endothelial Cells / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteolysis*
  • Scavenger Receptors, Class E / genetics
  • Scavenger Receptors, Class E / metabolism*
  • Transfection


  • 1, 3-di-(N-carboxybenzoyl-leucyl-leucyl)amino acetone
  • Dipeptides
  • Membrane Proteins
  • OLR1 protein, human
  • Olr1 protein, mouse
  • Scavenger Receptors, Class E
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • SPPL2a protein, human
  • SPPL2a protein, mouse
  • SPPL2b protein, human
  • SPPL2b protein, mouse
  • ADAM10 Protein
  • ADAM10 protein, human