Home > Publications Database > Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. > print

001     140611
005     20240321220837.0
024 7 _ |a 10.1084/jem.20171438
|2 doi
024 7 _ |a pmid:30819724
|2 pmid
024 7 _ |a pmc:PMC6446863
|2 pmc
024 7 _ |a 0022-1007
|2 ISSN
024 7 _ |a 1540-9358
|2 ISSN
024 7 _ |a 1540-9538
|2 ISSN
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037 _ _ |a DZNE-2020-06933
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Mentrup, Torben
|b 0
245 _ _ |a Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
260 _ _ |a New York, NY
|c 2019
|b Rockefeller Univ. Press
264 _ 1 |3 online
|2 Crossref
|b Rockefeller University Press
|c 2019-02-28
264 _ 1 |3 print
|2 Crossref
|b Rockefeller University Press
|c 2019-04-01
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
|m journal
|0 PUB:(DE-HGF)16
|s 1589472013_7797
|2 PUB:(DE-HGF)
336 7 _ |a ARTICLE
|2 BibTeX
336 7 _ |a JOURNAL_ARTICLE
|2 ORCID
336 7 _ |a Journal Article
|0 0
|2 EndNote
520 _ _ |a 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.
536 _ _ |a 342 - Disease Mechanisms and Model Systems (POF3-342)
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|c POF3-342
|f POF III
|x 0
542 _ _ |i 2019-02-28
|2 Crossref
|u http://www.rupress.org/terms/
542 _ _ |i 2019-09-30
|2 Crossref
|u https://creativecommons.org/licenses/by-nc-sa/4.0/
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 2 |a ADAM10 Protein: metabolism
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: metabolism
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: genetics
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: metabolism
|2 MeSH
650 _ 2 |a Atherosclerosis: metabolism
|2 MeSH
650 _ 2 |a Dipeptides: pharmacology
|2 MeSH
650 _ 2 |a Endothelial Cells: metabolism
|2 MeSH
650 _ 2 |a HEK293 Cells
|2 MeSH
650 _ 2 |a HeLa Cells
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Membrane Proteins: genetics
|2 MeSH
650 _ 2 |a Membrane Proteins: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Proteolysis
|2 MeSH
650 _ 2 |a Scavenger Receptors, Class E: genetics
|2 MeSH
650 _ 2 |a Scavenger Receptors, Class E: metabolism
|2 MeSH
650 _ 2 |a Transfection
|2 MeSH
700 1 _ |a Theodorou, Kosta
|b 1
700 1 _ |a Cabrera-Cabrera, Florencia
|b 2
700 1 _ |a Helbig, Andreas O
|b 3
700 1 _ |a Happ, Kathrin
|b 4
700 1 _ |a Gijbels, Marion
|b 5
700 1 _ |a Gradtke, Ann-Christine
|b 6
700 1 _ |a Rabe, Björn
|b 7
700 1 _ |a Fukumori, Akio
|0 P:(DE-2719)2810765
|b 8
|u dzne
700 1 _ |a Steiner, Harald
|0 P:(DE-2719)2000023
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700 1 _ |a Tholey, Andreas
|b 10
700 1 _ |a Fluhrer, Regina
|0 P:(DE-2719)2000007
|b 11
|u dzne
700 1 _ |a Donners, Marjo
|b 12
700 1 _ |a Schröder, Bernd
|0 P:(DE-HGF)0
|b 13
|e Corresponding author
773 1 8 |a 10.1084/jem.20171438
|b : Rockefeller University Press, 2019-02-28
|n 4
|p 807-830
|3 journal-article
|2 Crossref
|t Journal of Experimental Medicine
|v 216
|y 2019
|x 0022-1007
773 _ _ |a 10.1084/jem.20171438
|g Vol. 216, no. 4, p. 807 - 830
|0 PERI:(DE-600)1477240-1
|n 4
|q 216:4<807 - 830
|p 807-830
|t Journal of experimental medicine
|v 216
|y 2019
|x 0022-1007
856 7 _ |2 Pubmed Central
|u http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446863
909 C O |o oai:pub.dzne.de:140611
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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913 1 _ |a DE-HGF
|b Forschungsbereich Gesundheit
|l Erkrankungen des Nervensystems
|1 G:(DE-HGF)POF3-340
|0 G:(DE-HGF)POF3-342
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914 1 _ |y 2019
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