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
N1 - Funding Information:
This work was supported by the Deutsche Forschung-sgemeinschaft as part of the SFB877 (project B7 to B. Schröder, and project Z2 to A.O. Helbig and A. Tholey), and the research group FOR2290 (projects FL 635/3-1 to R. Fluhrer, and STE847/ 4-1 to H. Steiner), as well as grants SCHR 1284/1-1 and SCHR1284/ 2-1 (to B. Schröder) and FL 635/2-1 (to R. Fluhrer). M. Donners and K. Theodorou were supported by the the Netherlands Heart Foundation (Dr. E. Dekker grant 2012T079). The authors declare no competing financial interests.
Funding Information:
We thank Sebastian Held, Marlies Rusch, and Martina Haug-Kröper for excellent technical assistance. We are grateful to Tatsuya Sawamura (National Cerebral and Cardiovascular Center, Osaka, Japan), Michael Engelke (University of Göttingen, Göttingen, Germany), and Hanjoong Jo (Emory University, Atlanta, GA) for plasmids and cell lines. We thank Kristiaan Wouters (Maastricht University, Maastricht, Netherlands) for providing material from LDL receptor-deficient mice. We are also grateful for support by the Z3 imaging unit of the SFB877.
Publisher Copyright:
© 2019 Mentrup et al.
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
SN - 0022-1007
VL - 216
SP - 807
EP - 830
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -