期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 21, 页码 8480-8489出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.006040
关键词
poxvirus; inflammasome; innate immunity; NF-kappa B (NF-KB); host-pathogen interaction; ASC-1; immune evasion; myxoma virus; PYRIN domain
资金
- Science Foundation Ireland [SFI-12/IA/1239]
- National Institutes of Health [R01 AI100987]
- Arizona State University
- Shaler Richardson Professorship Endowment
Among the repertoire of immunoregulatory proteins encoded by myxoma virus, M013 is a viral homologue of the viral pyrin domain-only protein (vPOP) family. In myeloid cells, M013 protein has been shown to inhibit both the inflammasome and NF-B signaling pathways by direct binding to ASC1 and NF-B1, respectively. In this study, a three-dimensional homology model of the M013 pyrin domain (PYD) was built based on similarities to known PYD structures. A distinctive feature of the deduced surface electrostatic map of the M013 PYD is the presence of a negatively region consisting of numerous aspartate and glutamate residues in close proximity. Single-site mutations of aspartate and glutamate residues reveal their role in interactions with ASC-1. The biological significance of charge complementarity in the M013-ASC-1 interaction was further confirmed by functional assays of caspase-1 activation and subsequent secretion of cytokines. M013 also has a unique 33-residue C-terminal tail that follows the N-terminal PYD, and it is enriched in positively charged residues. Deletion of the tail of M013 significantly inhibited the interactions between M013 and NF-B1, thus compromising the ability of the viral protein to suppress the secretion of pro-inflammatory cytokines. These results demonstrate that vPOP M013 exploits distinct structural motifs to regulate both the inflammasome and NF-B pathways.
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