TY - JOUR
T1 - Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
AU - Mentrup, Torben
AU - Theodorou, Kosta
AU - Cabrera-Cabrera, Florencia
AU - Hethig, Andreas O.
AU - Happ, Kathrin
AU - Gijbels, Marion
AU - Gradtke, Ann-Christine
AU - Rabe, Bjoern
AU - Fukumori, Akio
AU - Steiner, Harald
AU - Tholey, Andreas
AU - Fluhrer, Regina
AU - Donners, Marjo
AU - Schroeder, Bernd
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
KW - LOW-DENSITY-LIPOPROTEIN
KW - NF-KAPPA-B
KW - PEPTIDASE-LIKE 2A
KW - OXIDIZED LDL RECEPTOR-1
KW - TISSUE GROWTH-FACTOR
KW - PROTEASE SPPL2A
KW - DENDRITIC CELLS
KW - OX-LDL
KW - PROMOTES ATHEROSCLEROSIS
KW - NUCLEAR TRANSLOCATION
U2 - 10.1084/jem.20171438
DO - 10.1084/jem.20171438
M3 - Article
VL - 216
SP - 807
EP - 830
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -