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

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 Alzheimers 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.

Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

“…We therefore sought to selectively inhibit TREM2 cleavage without affecting shedding of other ADAM10/17 substrates. We and others have previously identified the cleavage site of TREM2 after His 157 within the stalk region of TREM2 (Feuerbach et al , ; Schlepckow et al , ; Thornton et al , ) (Fig A). In this study, we screened for monoclonal antibodies binding to the stalk region encompassing the cleavage site with the purpose of stabilizing membrane‐bound TREM2 and selectively enhancing TREM2‐dependent protective functions in microglia.…”

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

“…Furthermore, weak stimulation of TREM2 is anti‐inflammatory and can suppress TLR4‐induced pro‐inflammatory cytokine production, via a poorly characterised mechanism regulated by JNK (Hamerman et al, ; Zhong et al, ; Zhong, Zhang, et al, ). Aside from its role as a membrane receptor, TREM2 undergoes regulated intramembrane proteolysis, with the entire ectodomain shed by the disintegrin and metalloproteinase ADAM 10 or ADAM17 metalloproteinases, depending on the cell model used (Feuerbach et al, ; Thornton et al, ). The secreted ectodomain, soluble TREM2 (sTREM2), appears to have its own distinct biological activity (Kober & Brett, ; Zhong, Chen, et al, ).…”

Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ1-42

“…Glycosaminoglycans (GAGs) engage the basic patch [15]. Soluble TREM2 (sTREM2) can be produced by proteolytic cleavage by ADAM10 and ADAM17 [6,7] or by alternate transcripts [8]. Its levels appear to be modulated by MS4A4A [45].…”

“…AD mouse models and microglia culture studies indicate that TREM2 engages extracellular ligands to transduce signals that regulate microglial functions such as inflammatory cytokine production, migration, proliferation, phagocytosis, survival, and compaction of Aβ plaques [4,5]. In addition to the receptor form, TREM2 can also be proteolytically released [6,7] or alternatively transcribed [8] as a soluble version (sTREM2), which is detectable in human CSF [9]. Little is known regarding the in vivo function of sTREM2; however, it is generally associated with beneficial phenotypes.…”