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Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages
- Source :
- The FASEB journal 34(5), 6675-6687 (2020). doi:10.1096/fj.201902183R
- Publication Year :
- 2019
-
Abstract
- The triggering receptor expressed on myeloid cells 2 (TREM2) is a multifunctional surface protein that affects survival, migration, and phagocytic capacity of myeloid cells. Soluble TREM2 levels were found to be increased in early stages of sporadic and familial Alzheimer's disease (AD) probably reflecting a defensive microglial response to some initial brain damage. The disintegrin and metalloproteases (ADAM) 10 and 17 were identified as TREM2 sheddases. We demonstrate that meprin β is a direct TREM2 cleaving enzyme using ADAM10/17 deficient HEK293 cells. LC‐MS/MS analysis of recombinant TREM2 incubated with meprin β revealed predominant cleavage between Arg136 and Asp137, distant to the site identified for ADAM10/17. We further demonstrate that the metalloprotease meprin β cleaves TREM2 on macrophages concomitant with decreased levels of soluble TREM2 in the serum of Mep1b−/− mice compared to WT controls. Isolated BMDMs from Mep1b−/− mice showed significantly increased full‐length TREM2 levels and enhanced phagocytosis efficiency compared to WT cells. The diminished constitutive shedding of TREM2 on meprin β deficient macrophages could be rescued by ADAM stimulation through LPS treatment. Our data provide evidence that meprin β is a TREM2 sheddase on macrophages and suggest that multiple proteases may be involved in the generation of soluble TREM2.
- Subjects :
- 0301 basic medicine
Male
Proteases
metabolism [Arginine]
Phagocytosis
ADAM10
cytology [Macrophages]
Arginine
Biochemistry
03 medical and health sciences
Mice
0302 clinical medicine
genetics [Membrane Glycoproteins]
ddc:570
Genetics
Disintegrin
genetics [Receptors, Immunologic]
Animals
Receptors, Immunologic
Receptor
Molecular Biology
Mice, Knockout
Metalloproteinase
Aspartic Acid
Membrane Glycoproteins
biology
TREM2
Chemistry
Macrophages
metabolism [Receptors, Immunologic]
Metalloendopeptidases
physiology [Macrophages]
Sheddase
metabolism [Aspartic Acid]
Molecular biology
030104 developmental biology
biology.protein
physiology [Metalloendopeptidases]
metabolism [Membrane Glycoproteins]
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- ISSN :
- 15306860
- Volume :
- 34
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental BiologyREFERENCES
- Accession number :
- edsair.doi.dedup.....2efd92d4a78dc7c9c7d36606c5819495