Open AccessTREM 2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant
Author(s) -
Thornton Peter,
Sevalle Jean,
Deery Michael J,
Fraser Graham,
Zhou Ye,
Ståhl Sara,
Franssen Elske H,
Dodd Roger B,
Qamar Seema,
Gomez PerezNievas Beatriz,
Nicol Louise SC,
Eketjäll Susanna,
Revell Jefferson,
Jones Clare,
Billinton Andrew,
St GeorgeHyslop Peter H,
Chessell Iain,
Crowther Damian C
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201707673
Subject(s) - cleavage (geology) , disease , chemistry , medicine , biology , pathology , paleontology , fracture (geology)
We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 ( TREM 2) from primary cultures of human macrophages, murine microglia and TREM 2‐expressing human embryonic kidney ( HEK 293) cells. In all cell types, a soluble 17 kDa N‐terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and si RNA targeting ADAM 10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM 17 si RNA did not block TREM 2 shedding. Peptidomimetic protease inhibitors highlighted a possible cleavage site, and mass spectrometry confirmed that shedding occurred predominantly at the H157‐S158 peptide bond for both wild‐type and H157Y human TREM 2 and for the wild‐type murine orthologue. Crucially, we also show that the Alzheimer's disease‐associated H157Y TREM 2 variant was shed more rapidly than wild type from HEK 293 cells, possibly by a novel, batimastat‐ and ADAM 10‐si RNA ‐independent, sheddase activity. These insights offer new therapeutic targets for modulating the innate immune response in Alzheimer's and other neurological diseases.