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@ARTICLE{Mentrup:140611,
      author       = {Mentrup, Torben and Theodorou, Kosta and Cabrera-Cabrera,
                      Florencia and Helbig, Andreas O and Happ, Kathrin and
                      Gijbels, Marion and Gradtke, Ann-Christine and Rabe, Björn
                      and Fukumori, Akio and Steiner, Harald and Tholey, Andreas
                      and Fluhrer, Regina and Donners, Marjo and Schröder, Bernd},
      title        = {{A}therogenic {LOX}-1 signaling is controlled by
                      {SPPL}2-mediated intramembrane proteolysis.},
      journal      = {Journal of experimental medicine},
      volume       = {216},
      number       = {4},
      issn         = {0022-1007},
      address      = {New York, NY},
      publisher    = {Rockefeller Univ. Press},
      reportid     = {DZNE-2020-06933},
      pages        = {807-830},
      year         = {2019},
      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.},
      keywords     = {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},
      cin          = {AG Steiner / AG Fluhrer},
      ddc          = {610},
      cid          = {I:(DE-2719)1110000-1 / I:(DE-2719)1110000-2},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30819724},
      pmc          = {pmc:PMC6446863},
      doi          = {10.1084/jem.20171438},
      url          = {https://pub.dzne.de/record/140611},
}