Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Arnold, Philipp; Boll, Inga; Rothaug, Michelle; Schumacher, Neele; Schmidt, Frederike; Wichert, Rielana; Schneppenheim, Janna; Lokau, Juliane; Pickhinke, Ute; Koudelka, Tomas; Tholey, Andreas; Rabe, Björn; Scheller, Jürgen; Lucius, Ralph; Garbers, Christoph; Rose-John, Stefan; Becker‐Pauly, Christoph

doi:10.1038/srep44053

Cited by 51 publications

(61 citation statements)

References 83 publications

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“…Several cell surface proteins were found to be similarly cleaved by ADAM10/17 and meprin β 26,27 . Therefore, we hypothesized that TREM2 may also be a shared substrate and investigated its shedding by meprin β.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, inhibition experiments revealed only minor contribution of ADAM10 in these cells 21 . The metalloprotease meprin β can cleave several cell surface proteins similar to ADAM10/17 26,27 . Hence, we investigated if TREM2 may also be a shared substrate and analyzed its shedding by meprin β.…”

Section: Discussionmentioning

confidence: 99%

“…Meprin β belongs to the astacin family of metalloproteinases and exhibits striking cleavage specificity with a preference for negatively charged amino acids around the scissile bond 25 . Similar to ADAM10 and ADAM17, meprin β was found to cleave several cell surface proteins such as the amyloid precursor protein (APP) at the β‐secretase site, 26 the IL‐6 receptor on human granulocytes to induce IL‐6 trans‐signaling, 27 and CD99 on endothelial cells, thereby promoting transendothelial cell migration 28,29 …”

Section: Introductionmentioning

confidence: 99%

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Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages

et al. 2020

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages

et al. 2020

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“…Conclusively, we identified a complex proteolytic interaction between meprin β and ADAM proteases within the proteolytic web that controls protease activity at the cell surface, thereby influencing conversion of further substrates. Because ADAM proteases and meprin β also share common substrates, such as APP (6, 21) or the IL‐6 receptor (4, 53), it will be interesting to further investigate those cleavage events under physiologic and pathologic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Meprin β and certain ADAMs have several common substrates, such as APP (26) or the IL‐6 receptor (4). Furthermore, these proteases are part of a complex protease web that regulates their localization and back‐and‐forth activity.…”

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confidence: 99%

Meprin β induces activities of A disintegrin and metalloproteinases 9, 10, and 17 by specific prodomain cleavage

Wichert¹,

Scharfenberg²,

Colmorgen³

et al. 2019

The FASEB Journal

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Meprin β is a membrane‐bound metalloprotease involved in extracellular matrix assembly and inflammatory processes in health and disease. A disintegrin and metalloproteinase (ADAM)10 and ADAM17 are physiologic relevant sheddases of inactive promeprin β, which influences its substrate repertoire and subsequent biologic functions. Proteomic analysis also revealed several ADAMs as putative meprin β substrates. Here, we demonstrate specific N‐terminal processing of ADAM9, 10, and 17 by meprin β and identify cleavage sites within their prodomains. Because ADAM prodomains can act as specific inhibitors, we postulate a role for meprin β in the regulation of ADAM activities. Indeed, prodomain cleavage by meprin β caused increased ADAM protease activities, as observed by peptide‐based cleavage assays and demonstrated by increased ectodomain shedding activity. Direct interaction of meprin β and ADAM proteases could be shown by immunofluorescence microscopy and immunoprecipitation experiments. As demonstrated by a bacterial activator of meprin β and additional measurement of TNF‐α shedding on bone marrow‐derived macrophages, meprin β/ADAM protease interactions likely influence inflammatory conditions. Thus, we identified a novel proteolytic pathway of meprin β with ADAM proteases to control protease activities at the cell surface as part of the protease web.—Wichert, R., Scharfenberg, F., Colmorgen, C., Koudelka, T., Schwarz, J., Wetzel, S., Potempa, B., Potempa, J., Bartsch, J. W., Sagi, I., Tholey, A., Saftig, P., Rose‐John, S., Becker‐Pauly, C. Meprin β induces activities of A disintegrin and metalloproteinases 9, 10, and 17 by specific prodomain cleavage. FASEB J. 33, 11925‐11940 (2019). http://www.fasebj.org

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Meprin and ADAM proteases as triggers of systemic inflammation in sepsis

Rahn

Becker‐Pauly

2021

FEBS Letters

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Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead to organ failure and death, and their increasing incidence represents a major issue for the healthcare system. Protease‐mediated ectodomain shedding of cytokines and their receptors represents a central mechanism in the regulation of inflammatory responses. The metalloprotease A disintegrin and metalloproteinase (ADAM) 17 is the best‐characterized ectodomain sheddase capable of releasing TNF‐α and soluble IL‐6 receptor, which are decisive factors of systemic inflammation. Recently, meprin metalloproteases were also identified as IL‐6 receptor sheddases and activators of the pro‐inflammatory cytokines IL‐1β and IL‐18. In different mouse models of SID, particularly those mimicking a sepsis‐like phenotype, ADAM17 and meprins have been found to promote disease progression. In this review, we summarize the role of ADAM10, ADAM17, and meprins in the onset and progression of sepsis and discuss their potential as therapeutic targets.

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Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

Cited by 51 publications

References 83 publications

Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages

Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages

Meprin β induces activities of A disintegrin and metalloproteinases 9, 10, and 17 by specific prodomain cleavage

Meprin and ADAM proteases as triggers of systemic inflammation in sepsis

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