Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages

Berner, Dennis Kristopher; Wessolowski, Luisa; Armbrust, Fred; Schneppenheim, Janna; Schlepckow, Kai; Koudelka, Tomas; Scharfenberg, Franka; Lucius, Ralph; Tholey, Andreas; Kleinberger, Gernot; Haass, Christian; Arnold, Philipp; Becker‐Pauly, Christoph

doi:10.1096/fj.201902183r

Cited by 23 publications

(19 citation statements)

References 52 publications

(86 reference statements)

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“…We devised a sandwich ELISA, capturing sTREM2 from cell culture supernatants, and confirmed that scFvs were not masking the sTREM2 epitopes required by the ELISA capture and detection antibodies ( Figure S5). Recently another metalloprotease, meprin β, was shown to cleave TREM2, with the main cleavage site between Arg136 and Asp137 (Berner et al, 2020). We confirmed that both the ectodomain as well as a sequence of stalk C-terminal to Ala138 were required for detection in our ELISA protocol.…”

Section: Scfv-3 and Scfv-4 Reduce Shedding Of Strem2 From Hek293 Cellsupporting

confidence: 78%

Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain

Szykowska¹,

Chen

Smith

et al. 2021

Preprint

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Single point mutations in TREM2, a receptor expressed by microglia in the brain, are associated with an increased risk of neurodegeneration including Alzheimer's disease. Numerous studies support a role for TREM2 in sensing damaging stimuli and triggering signalling cascades necessary for neuroprotection. Despite its significant role, ligands and regulators of TREM2 activation, and the mechanisms governing TREM2-dependent responses and its cleavage from the membrane, remain poorly characterised. Here, we present phage display generated scFv antibody binders to human TREM2 ectodomain. Co-crystal structures revealed the binding of two scFvs to an epitope on the globular TREM2 domain distal to the putative ligand-binding site. Enhanced functional activity was observed for oligomeric scFv species which inhibited the production of soluble TREM2 in a HEK293 cell model. We hope that detailed characterisation of their epitopes and properties will facilitate the use of these renewable binders as structural and functional biology tools for TREM2 research.

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Section: Scfv-3 and Scfv-4 Reduce Shedding Of Strem2 From Hek293 Cellsupporting

confidence: 78%

Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain

Szykowska¹,

Chen

Smith

et al. 2021

Preprint

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“…One such sheddase, meprin β (Mβ), is a widespread metallopeptidase (MP) that is highly abundant on the surface of various cell types (2). Mβ sheds surface proteins such as growth factors, cytokines, receptors, amyloid precursor protein (APP; at its β-secretase site), and other MPs (1,3,4). It is therefore essential for processes in which deregulation leads to neurodegenerative diseases, inflammatory bowel disease, fibrosis, nephritis, and cancer (2).…”

mentioning

confidence: 99%

The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B

Eckhard

Körschgen

Wiegen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Meprin β (Mβ) is a multidomain type-I membrane metallopeptidase that sheds membrane-anchored substrates, releasing their soluble forms. Fetuin-B (FB) is its only known endogenous protein inhibitor. Herein, we analyzed the interaction between the ectodomain of Mβ (MβΔC) and FB, which stabilizes the enzyme and inhibits it with subnanomolar affinity. The MβΔC:FB crystal structure reveals a ∼250-kDa, ∼160-Å polyglycosylated heterotetrameric particle with a remarkable glycan structure. Two FB moieties insert like wedges through a “CPDCP trunk” and two hairpins into the respective peptidase catalytic domains, blocking the catalytic zinc ions through an “aspartate switch” mechanism. Uniquely, the active site clefts are obstructed from subsites S4 to S10′, but S1 and S1′ are spared, which prevents cleavage. Modeling of full-length Mβ reveals an EGF-like domain between MβΔC and the transmembrane segment that likely serves as a hinge to transit between membrane-distal and membrane-proximal conformations for inhibition and catalysis, respectively.

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“…These may be due to proteolytic mechanisms that promote cleavage and release of Trem2 from the eosinophil cell surface. Metalloproteases, including Meprin‐B, ADAM10, and ADAM17 promote the release of soluble Trem2 from the surface of myeloid cells 88–90 . Our findings might also be explained by the results of studies that address sequestration of immunoreactive Trem2 within the cell of origin; in this case, detection of immunoreactive Trem2 might require translocation of pre‐formed protein to the cell surface.…”

Section: Discussionmentioning

confidence: 82%

Differential expression of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) in tissue eosinophils

Sek

Percopo

Boddapati

et al. 2021

Journal of Leukocyte Biology

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No longer regarded simply as end‐stage cytotoxic effectors, eosinophils are now recognized as complex cells with unique phenotypes that develop in response stimuli in the local microenvironment. In our previous study, we documented eosinophil infiltration in damaged muscle characteristic of dystrophin‐deficient (mdx) mice that model Duchenne muscular dystrophy. Specifically, we found that eosinophils did not promote the generation of muscle lesions, as these persisted in eosinophil‐deficient mdx.PHIL mice. To obtain additional insight into these findings, we performed RNA sequencing of eosinophils isolated from muscle tissue of mdx, IL5tg, and mdx.IL5tg mice. We observed profound up‐regulation of classical effector proteins (major basic protein‐1, eosinophil peroxidase, and eosinophil‐associated ribonucleases) in eosinophils isolated from lesion‐free muscle from IL5tg mice. By contrast, we observed significant up‐regulation of tissue remodeling genes, including proteases, extracellular matrix components, collagen, and skeletal muscle precursors, as well as the immunomodulatory receptor, Trem2, in eosinophils isolated from skeletal muscle tissue from the dystrophin‐deficient mdx mice. Although the anti‐inflammatory properties of Trem2 have been described in the monocyte/macrophage lineage, no previous studies have documented its expression in eosinophils. We found that Trem2 was critical for full growth and differentiation of bone marrow‐derived eosinophil cultures and full expression of TLR4. Immunoreactive Trem2 was also detected on human peripheral blood eosinophils at levels that correlated with donor body mass index and total leukocyte count. Taken together, our findings provide important insight into the immunomodulatory and remodeling capacity of mouse eosinophils and the flexibility of their gene expression profiles in vivo.

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Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 23 publications

References 52 publications

Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain

Selection and structural characterisation of anti-TREM2 scFvs that reduce levels of shed ectodomain

The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B

Differential expression of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) in tissue eosinophils

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