Processing and secretion of guanylate binding protein-1 depend on inflammatory caspase activity

Naschberger E, Geissdorfer W, Bogdan C, Tripal P, Kremmer E, Stürzl M, Britzen-Laurent N (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 21

Pages Range: 1954-1966

Journal Issue: 9

DOI: 10.1111/jcmm.13116

Abstract

Human guanylate binding protein-1 (GBP-1) belongs to the family of large GTPases. The expression of GBP-1 is inducible by inflammatory cytokines, and the protein is involved in inflammatory processes and host defence against cellular pathogens. GBP-1 is the first GTPase which was described to be secreted by eukaryotic cells. Here, we report that precipitation of GBP-1 with GMP-agarose from cell culture supernatants co-purified a 47-kD fragment of GBP-1 (p47-GBP-1) in addition to the 67-kD full-length form. MALDI-TOF sequencing revealed that p47-GBP-1 corresponds to the C-terminal helical part of GBP-1 and lacks most of the globular GTPase domain. In silico analyses of protease target sites, together with cleavage experiments in vitro and in vivo, showed that p67-GBP-1 is cleaved by the inflammatory caspases 1 and 5, leading to the formation of p47-GBP-1. Furthermore, the secretion of p47-GBP-1 was found to occur via a non-classical secretion pathway and to be dependent on caspase-1 activity but independent of inflammasome activation. Finally, we showed that p47-GBP-1 represents the predominant form of secreted GBP-1, both in cell culture supernatants and, in vivo, in the cerebrospinal fluid of patients with bacterial meningitis, indicating that it may represent the biologically active form of extracellular GBP-1. These findings confirm the involvement of caspase-1 in non-classical secretion mechanisms and open novel perspectives for the extracellular function of secreted GBP-1.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich Germany (DE)

How to cite

APA:

Naschberger, E., Geissdorfer, W., Bogdan, C., Tripal, P., Kremmer, E., Stürzl, M., & Britzen-Laurent, N. (2017). Processing and secretion of guanylate binding protein-1 depend on inflammatory caspase activity. Journal of Cellular and Molecular Medicine, 21(9), 1954-1966. https://dx.doi.org/10.1111/jcmm.13116

MLA:

Naschberger, Elisabeth, et al. "Processing and secretion of guanylate binding protein-1 depend on inflammatory caspase activity." Journal of Cellular and Molecular Medicine 21.9 (2017): 1954-1966.

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