Co-regulation of NF-kappaB and inflammasome-mediated inflammatory responses by myxoma virus pyrin domain-containing protein M013.

Abstract

NF-kappaB and inflammasomes both play central roles in orchestrating anti-pathogen responses by rapidly inducing a variety of early-response cytokines and chemokines following infection. Myxoma virus (MYXV), a pathogenic poxvirus of rabbits, encodes a member of the cellular pyrin domain (PYD) superfamily, called M013. The viral M013 protein was previously shown to bind host ASC-1 protein and inhibit the cellular inflammasome complex that regulates the activation and secretion of caspase 1-regulated cytokines such as IL-1beta and IL-18. Here, we report that human THP-1 monocytic cells infected with a MYXV construct deleted for the M013L gene (vMyxM013-KO), in stark contrast to the parental MYXV, rapidly induce high levels of secreted pro-inflammatory cytokines like TNF, IL-6, and MCP-1, all of which are regulated by NF-kappaB. The induction of these NF-kappaB regulated cytokines following infection with vMyxM013-KO was also confirmed in vivo using THP-1 derived xenografts in NOD-SCID mice. vMyxM013-KO virus infection specifically induced the rapid phosphorylation of IKK and degradation of IkappaBalpha, which was followed by nuclear translocation of NF-kappaB/p65. Even in the absence of virus infection, transiently expressed M013 protein alone inhibited cellular NF-kappaB-mediated reporter gene expression and nuclear translocation of NF-kappaB/p65. Using protein/protein interaction analysis, we show that M013 protein also binds directly with cellular NF-kappaB1, suggesting a direct physical and functional linkage between NF-kappaB1 and ASC-1. We further demonstrate that inhibition of the inflammasome with a caspase-1 inhibitor did not prevent the induction of NF-kappaB regulated cytokines following infection with vMyxM013-KO virus, but did block the activation of IL-1beta. Thus, the poxviral M013 inhibitor exerts a dual immuno-subversive role in the simultaneous co-regulation of both the cellular inflammasome complex and NF-kappaB-mediated pro-inflammatory responses.

• Authors: Masmudur M Rahman, Mohamed R Mohamed, Manbok Kim, Sherin Smallwood, Grant McFadden
• Journal: PLoS pathogens (PLoS Pathog) Vol. 5 Issue 10 Pg. e1000635 (Oct 2009) ISSN: 1553-7374 [Electronic] United States
• PMID: 19851467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytoskeletal Proteins
• Inflammation Mediators
• MEFV protein, human
• Mefv protein, mouse
• NF-kappa B
• Pyrin
• Viral Proteins

Topics

• Animals
• Cells, Cultured
• Cytoskeletal Proteins (chemistry, genetics)
• Female
• HeLa Cells
• Host-Pathogen Interactions (genetics)
• Humans
• Immunity, Innate (drug effects, genetics)
• Inflammation (chemically induced, genetics, virology)
• Inflammation Mediators (pharmacology, physiology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Myxoma virus (chemistry, genetics, pathogenicity)
• NF-kappa B (pharmacology, physiology)
• Organisms, Genetically Modified
• Protein Structure, Tertiary (genetics)
• Pyrin
• Rabbits
• Signal Transduction (drug effects, genetics)
• Viral Proteins (genetics)
• Xenograft Model Antitumor Assays