Mucus Detachment by Host Metalloprotease Meprin β Requires Shedding of Its Inactive Pro-form, which Is Abrogated by the Pathogenic Protease RgpB

Wichert, Rielana; Ermund, Anna; Schmidt, Stefanie; Schweinlin, Matthias; Książek, Mirosław; Arnold, Philipp; Knittler, Katharina; Wilkens, Frederike; Potempa, Barbara; Rabe, Björn; Stirnberg, Marit; Lucius, Ralph; Bartsch, Jörg W.; Nikolaus, Susanna; Falk-Paulsen, Maren; Rosenstiel, Philip; Metzger, Marco; Rose-John, Stefan; Potempa, Jan; Hansson, Gunnar C.; Dempsey, Peter J.; Becker‐Pauly, Christoph

doi:10.1016/j.celrep.2017.10.087

Cited by 32 publications

(66 citation statements)

References 61 publications

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“…For instance, binding of BACE1 to the adaptor protein GGA promotes degradation (Tesco et al , ) and this is blocked by a specific sugar modification, bisecting N‐acetylglucosamine (Kizuka et al , ). As an alternative to lysosomal degradation, classical sheddases may be shed themselves, e.g., ADAM10, BACE1, and meprin β (Hussain et al , ; Tousseyn et al , ), which may be considered a mechanism for inactivating a sheddase (Wichert et al , ).…”

Section: Regulation Of Sheddingmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

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Section: Regulation Of Sheddingmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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“…7). Besides ADAM10‐ and ADAM17‐mediated shedding of inactive promeprin β (8), we revealed that meprin β can boost the activity of ADAM proteases 9, 10, and 17. Virulence factors, such as RgpB, can activate membrane‐bound meprin β, thereby leading to pathologic conditions by changing its substrate repertoire as previously shown for the intestine (8).…”

Section: Resultsmentioning

confidence: 99%

“…We previously showed that meprin β activation and its shedding by ADAM10 and 17 are mutually exclusive events (8). This strict regulation of meprin β activity can be overridden by bacterial pathogens as demonstrated for the bacterial protease Arg‐ RgpB, which causes severe inflammation in the intestine (8). On the other hand, meprin β was shown to induce the production of proinflammatory cytokines in macrophages, including IL‐1b and IL‐18 (47, 48).…”

Section: Discussionmentioning

confidence: 99%

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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 a is shed by furin on the secretory pathway, oligomerized, and secreted into the extracellular space (1,2). Meprin b, on the other hand, stays at the cell membrane until it is shed by a disintegrin and metalloproteases (ADAMs) to reach a different subset of substrates (3,4). Shortly after discovery of meprins, it was shown that both proteases form heterodimers in mice and rats when coexpressed (1,5).…”

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confidence: 99%

Tethering soluble meprin α in an enzyme complex to the cell surface affects IBD‐associated genes

et al. 2019

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Biologic activity of proteases is mainly characterized by the substrate specificity, tissue distribution, and cellular localization. The human metalloproteases meprin α and meprin β share 41% sequence identity and exhibit a similar cleavage specificity with a preference for negatively charged amino acids. However, shedding of meprin α by furin on the secretory pathway makes it a secreted enzyme in comparison with the membrane‐bound meprin β. In this study, we identified human meprin α and meprin β as forming covalently linked membrane‐tethered heterodimers in the early endoplasmic reticulum, thereby preventing furin‐mediated secretion of meprin α. Within this newly formed enzyme complex, meprin α was able to be activated on the cell surface and detected by cleavage of a novel specific fluorogenic peptide substrate. However, the known meprin β substrates amyloid precursor protein and CD99 were not shed by membrane‐tethered meprin α. On the other hand, being linked to meprin α, activation of or substrate cleavage by meprin β on the cell surface was not altered. Interestingly, proteolytic activity of both proteases was increased in the heteromeric complex, indicating an increased proteolytic potential at the plasma membrane. Because meprins are susceptibility genes for inflammatory bowel disease (IBD), and to investigate the physiologic impact of the enzyme complex, we performed transcriptome analyses of intestinal mucosa from meprin‐knockout mice. Comparison of the transcriptional gene analysis data with gene analyses of IBD patients revealed that different gene subsets were dysregulated if meprin α was expressed alone or in the enzyme complex, demonstrating the physiologic and pathophysiological relevance of the meprin heterodimer formation.—Peters, F., Scharfenberg, F., Colmorgen, C., Armbrust, F., Wiehert, R., Arnold, P., Potempa, B., Potempa, J., Pietrzik, C. U., Häsler, R., Rosenstiel, P., Becker‐Pauly, C. Tethering soluble meprin α in an enzyme complex to the cell surface affects IBD‐associated genes. FASEB J. 33, 7490–7504 (2019). http://www.fasebj.org

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Mucus Detachment by Host Metalloprotease Meprin β Requires Shedding of Its Inactive Pro-form, which Is Abrogated by the Pathogenic Protease RgpB

Cited by 32 publications

References 61 publications

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

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

Tethering soluble meprin α in an enzyme complex to the cell surface affects IBD‐associated genes

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