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Processing and secretion of guanylate binding protein-1 depend on inflammatory caspase activity.
J. Cell. Mol. Med. 21, 1954-1966 (2017)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Huvec ; Gtpase ; Inflammation ; Secretion ; Caspase-1 ; Caspase-5 ; Endothelial Cells ; Guanylate Binding Protein ; Interferon; Endothelial-cells; Colorectal-carcinoma; Nucleotide-binding; Inducible Gtpases; Interferon-gamma; Granzyme-b; Activation; Gtp; Family; Interleukin-1-beta
ISSN (print) / ISBN
1582-1838
e-ISSN
1582-4934
Quellenangaben
Volume: 21,
Issue: 9,
Pages: 1954-1966
Publisher
Blackwell
Publishing Place
Hoboken
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CF Monoclonal Antibodies (CF-MAB)