Abstract
BackgroundTriggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. Mutations in TREM2 are associated with several diseases, including Nasu-Hakola disease, frontotemporal dementia, and Alzheimer’s disease (AD). TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis.FindingsWe show that inhibition of γ-secretase-dependent cleavage of the TREM2 C-terminal fragment in cellular membranes interferes with TREM2-dependent signaling and cellular function. Inhibition of γ-secretase decreases membrane-proximal signaling and intracellular Ca2+ response. Decreased signaling alters morphological changes and phagocytic activity of cells upon selective stimulation of TREM2.ConclusionsThe data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2-mediated signaling and, thus, a functional relation of two AD-associated proteins.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0479-9) contains supplementary material, which is available to authorized users.
Highlights
Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia
The data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2mediated signaling and, a functional relation of two Alzheimer’s disease (AD)-associated proteins
The triggering receptor expressed on myeloid cells-2 (TREM2) belongs to the immunoglobulin superfamily of cell surface receptors and is expressed on monocytederived cell types, including dendritic cells [1], osteoclasts, tissue macrophages, and microglia [2]
Summary
Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. To investigate the role of γ-secretase in TREM2dependent signaling, we expressed a TREM2 variant with an N-terminal myc tag and a C-terminal green fluorescent protein (GFP) tag together with its coreceptor DAP12. Western immunoblotting with anti-myc and antiGFP antibodies revealed expression of full-length TREM2 with the N- and C-terminal tags at ~60 kDa (Fig. 1a). Our previous data revealed that inhibition of γsecretase decreased the phosphorylation of the TREM2 co-receptor DAP12 and stabilized PIP2 levels at the plasma membrane, suggesting impaired activation of PLCγ [18].
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