Journal Article

DZNE-2020-06933

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.

Mentrup, T. ; Theodorou, K. ; Cabrera-Cabrera, F. ; Helbig, A. O. ; Happ, K. ; Gijbels, M. ; Gradtke, A.-C. ; Rabe, B. ; Fukumori, A.DZNE* ; Steiner, H.DZNE* ; Tholey, A. ; Fluhrer, R.DZNE* ; Donners, M. ; Schröder, B. (Corresponding author)

2019
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1084/jem.20171438

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.

Keyword(s): ADAM10 Protein: metabolism (MeSH) ; Amyloid Precursor Protein Secretases: metabolism (MeSH) ; Animals (MeSH) ; Aspartic Acid Endopeptidases: antagonists & inhibitors (MeSH) ; Aspartic Acid Endopeptidases: genetics (MeSH) ; Aspartic Acid Endopeptidases: metabolism (MeSH) ; Atherosclerosis: metabolism (MeSH) ; Dipeptides: pharmacology (MeSH) ; Endothelial Cells: metabolism (MeSH) ; HEK293 Cells (MeSH) ; HeLa Cells (MeSH) ; Humans (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; Proteolysis (MeSH) ; Scavenger Receptors, Class E: genetics (MeSH) ; Scavenger Receptors, Class E: metabolism (MeSH) ; Transfection (MeSH)

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Contributing Institute(s):

1. Biochemistry of γ-Secretase (AG Steiner)
2. Signal Peptide Peptidases as Models for γ-Secretase (AG Fluhrer)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection

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