Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 21, Issue 9, Pages 1954-1966Publisher
WILEY
DOI: 10.1111/jcmm.13116
Keywords
guanylate binding protein; interferon; GTPase; Secretion; Inflammation; caspase-1; caspase-5; endothelial cells; HUVEC
Categories
Funding
- ELAN-Fonds of the University of Erlangen-Nuremberg
- European Commission [FP7-Marie Curie IEF-221550]
- German Research Foundation [DFG: KFO257, FOR 2438, BR5196/2-1]
- emerging fields initiative (EFI) of the FAU
- W. Lutz Stiftung
- Interdisciplinary Center for Clinical Research (IZKF) of the Clinical Center Erlangen
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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.
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