Sequential Proteolytic Processing of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Protein by Ectodomain Shedding and γ-Secretase-dependent Intramembranous Cleavage

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. 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.