Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage

J Biol Chem. 2013 Nov 15;288(46):33027-36. doi: 10.1074/jbc.M113.517540. Epub 2013 Sep 27.

Abstract

Triggering receptor expressed on myeloid cells-2 (TREM2) and its signaling adaptor protein TYROBP/DAP12 play important roles in signal transduction in dendritic cells, osteoclasts, tissue macrophages, and microglia. Recently, TREM2 variants have been shown to be linked to late onset Alzheimer disease. Here, we demonstrate that TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. The C-terminal fragment (CTF) of TREM2 generated by ectodomain shedding is cleaved by γ-secretase. Importantly, pharmacologic and genetic γ-secretase inhibition resulted in accumulation of TREM2 CTF at the plasma membrane that also interacts with the signaling adaptor protein DAP12. Thus, the accumulated TREM2 CTF thereby might limit the interaction of DAP12 with the functional full-length receptor, resulting in decreased DAP12 phosphorylation and impaired metabolism of phosphatidylinositol 4,5-bisphosphate. Together, these data demonstrate γ-secretase-mediated intramembranous proteolysis of TREM2 and functionally link two Alzheimer disease-associated proteins in one signaling pathway.

Keywords: Alzheimer Disease; Intramembrane Proteolysis; Membrane; Presenilin; Protein Phosphorylation; Secretases; Signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • COS Cells
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / genetics
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphorylation / genetics
  • Protein Structure, Tertiary
  • Proteolysis*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • Membrane Glycoproteins
  • Membrane Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Immunologic
  • TREM2 protein, human
  • TYROBP protein, human
  • Amyloid Precursor Protein Secretases