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@ARTICLE{Ibach:157828,
      author       = {Ibach, Melanie and Mathews, Mona and Linnartz-Gerlach,
                      Bettina and Theil, Sandra and Kumar, Sathish and Feederle,
                      Regina and Brüstle, Oliver and Neumann, Harald and Walter,
                      Jochen},
      title        = {{A} reporter cell system for the triggering receptor
                      expressed on myeloid cells 2 reveals differential effects of
                      disease-associated variants on receptor signaling and
                      activation by antibodies against the stalk region.},
      journal      = {Glia},
      volume       = {69},
      number       = {5},
      issn         = {1098-1136},
      address      = {Bognor Regis [u.a.]},
      publisher    = {Wiley-Liss},
      reportid     = {DZNE-2021-01285},
      pages        = {1126 - 1139},
      year         = {2021},
      abstract     = {The triggering receptor expressed on myeloid cells 2
                      (TREM2) is an immune receptor expressed on myeloid-derived
                      cell types. The extracellular immunoglobulin-like domain of
                      TREM2 binds anionic ligands including Apolipoprotein E and
                      Amyloid-β. The transmembrane domain interacts with its
                      adaptor protein DAP12/TYROBP that is responsible for
                      propagation of downstream signaling upon ligand interaction.
                      Several sequence variants of TREM2 have been linked to
                      different neurodegenerative diseases including Alzheimer's
                      disease. Here, we generated HEK 293 Flp-In cell lines stably
                      expressing human TREM2 and DAP12 using a bicistronic
                      construct with a T2A linker sequence allowing initial
                      expression of both proteins in stoichiometric amounts. Cell
                      biological and biochemical analyses revealed transport of
                      TREM2 to the cell surface, and canonical sequential
                      proteolytic processing and shedding of TREM2 (sTREM2). The
                      functionality of this cell system was demonstrated by
                      detection of phosphorylated spleen tyrosine kinase (SYK)
                      upon stimulation of TREM2 with the anionic membrane lipid
                      phosphatidylserine or anti-TREM2 antibodies. Using this cell
                      model, we demonstrated impaired signaling of disease
                      associated TREM2 variants. We also identified a monoclonal
                      antibody against the stalk region of TREM2 with agonistic
                      activity. Activation of TREM2-DAP12 signaling with the
                      monoclonal antibody and the partial loss of function of
                      disease associated variants were recapitulated in induced
                      pluripotent stem cell derived microglia. Thus, this reporter
                      cell model represents a suitable experimental system to
                      investigate signaling of TREM2 variants, and for the
                      identification of ligands and compounds that modulate
                      TREM2-DAP12 signaling. MAIN POINTS: Disease associated
                      variants impair the signaling activity of TREM2 by distinct
                      mechanisms. Targeting the stalk region of TREM2 with
                      bivalent antibodies activates TREM2 signaling.},
      keywords     = {Alzheimer Disease / Antibodies, Monoclonal / Carrier
                      Proteins / HEK293 Cells / Humans / Ligands / Membrane
                      Glycoproteins: genetics / Microglia / Myeloid Cells /
                      Receptors, Immunologic: genetics / TREM2 variants (Other) /
                      agonistic antibody (Other) / reporter system (Other) /
                      signaling (Other)},
      cin          = {AG Feederle / AG Vorberg},
      ddc          = {610},
      cid          = {I:(DE-2719)1140004 / I:(DE-2719)1013004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33314333},
      doi          = {10.1002/glia.23953},
      url          = {https://pub.dzne.de/record/157828},
}