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ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157

Feuerbach, Dominik and Schindler, Patrick and Barske, Carmen and Joller, Stefanie and Beng-Louka, Edwige and Worringer, Katie and Kommineni, Sravya and Kaykas, Ajamete and Ho, Daniel and Welzenbach, Karl and Elain, Gaelle and Klein, Laurent and Mir, Anis Khusro and Farady, Christopher and Nakamura, MC and Hsieh, CL and Aichholz, Reiner and Popp, Simone and George, Nathalie and Neumann, Ulf (2017) ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157. Neuroscience letter.

Abstract

Triggering receptor expressed in myeloid cells (TREM2) is a member of the immunoglobulin superfamily and is expressed in macrophages, dendritic cells, microglia, and osteoclasts. TREM2 plays a role in phagocytosis, regulates release of cytokine, contributes to microglia maintenance, and its ectodomain is shed from the cell surface. Using both pharmacological and genetic approaches we report here that the main protease contributing to the release of TREM2 ectodomain is ADAM17, (a disintegrin and metalloproteinase domain containing protein, also called TACE, TNFα converting enzyme) while ADAM10 plays a minor role. Using mutational analysis, we demonstrate that the main cleavage site of the sheddases is located within the stalk region of TREM2 proximal to the plasma membrane. Complementary biochemical experiments reveal that cleavage occurs between histidine 157 and serine 158. Shedding is not altered for the R47H-mutated TREM2 protein that confers an increased risk for the development of Alzheimer’s disease. O-glycosylation is detected within the stalk region, but distant to the cleavage site. These findings reveal a link between shedding of TREM2 and its regulation during inflammatory conditions or chronic neurodegenerative disease like AD in which activity or expression of sheddases might be altered.

Item Type: Article
Date Deposited: 20 Oct 2017 00:45
Last Modified: 20 Oct 2017 00:45
URI: https://oak.novartis.com/id/eprint/32730

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