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

• Published in: The FASEB journal 2019-11, Vol.33 (11), p.11925-11940
• Main Authors: Wichert, Rielana, Scharfenberg, Franka, Colmorgen, Cynthia, Koudelka, Tomas, Schwarz, Jeanette, Wetzel, Sebastian, Potempa, Barbara, Potempa, Jan, Bartsch, Jörg W., Sagi, Irit, Tholey, Andreas, Saftig, Paul, Rose‐John, Stefan, Becker‐Pauly, Christoph
• Format: Article
• Language: English
• Subjects: ADAM; inflammation; proteolysis; zymogen activation
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201801371R

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). www.fasebj.org