Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection.
<h4>Unlabelled</h4>Single stranded RNA (ssRNA) virus infection activates the retinoic acid inducible gene I (RIG-I)- mitochondrial antiviral signaling (MAVS) complex, a complex that coordinates the host innate immune response via the NF-kappaB and IRF3 pathways. Recent work has shown tha...
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Public Library of Science (PLoS)
2009-11-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0008079&type=printable |
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| author | Ping Liu Muping Lu Bing Tian Kui Li Roberto P Garofalo Deborah Prusak Thomas G Wood Allan R Brasier |
| author_facet | Ping Liu Muping Lu Bing Tian Kui Li Roberto P Garofalo Deborah Prusak Thomas G Wood Allan R Brasier |
| author_sort | Ping Liu |
| collection | DOAJ |
| description | <h4>Unlabelled</h4>Single stranded RNA (ssRNA) virus infection activates the retinoic acid inducible gene I (RIG-I)- mitochondrial antiviral signaling (MAVS) complex, a complex that coordinates the host innate immune response via the NF-kappaB and IRF3 pathways. Recent work has shown that the IkappaB kinase (IKK)gamma scaffolding protein is the final common adapter protein required by RIG-I.MAVS to activate divergent rate-limiting kinases downstream controlling the NF-kappaB and IRF3 pathways. Previously we discovered a ubiquitous IKKgamma splice-variant, IKKgammaDelta, that exhibits distinct signaling properties.<h4>Methodology/principal findings</h4>We examined the regulation and function of IKKgamma splice forms in response to ssRNA virus infection, a condition that preferentially induces full length IKKgamma-WT mRNA expression. In IKKgammaDelta-expressing cells, we found increased viral translation and cytopathic effect compared to those expressing full length IKKgamma-WT. IKKgammaDelta fails to support viral-induced IRF3 activation in response to ssRNA infections; consequently type I IFN production and the induction of anti-viral interferon stimulated genes (ISGs) are significantly attenuated. By contrast, ectopic RIG-I.MAVS or TNFalpha-induced canonical NF-kappaB activation is preserved in IKKgammaDelta expressing cells. Increasing relative levels of IKKgamma-WT to IKKgammaDelta (while keeping total IKKgamma constant) results in increased type I IFN expression. Conversely, overexpressing IKKgammaDelta (in a background of constant IKKgamma-WT expression) shows IKKgammaDelta functions as a dominant-negative IRF3 signaling inhibitor. IKKgammaDelta binds both IKK-alpha and beta, but not TANK and IKKepsilon, indicating that exon 5 encodes an essential TANK binding domain. Finally, IKKgammaDelta displaces IKKgammaWT from MAVS explaining its domainant negative effect.<h4>Conclusions/significance</h4>Relative endogenous IKKgammaDelta expression affects cellular selection of inflammatory/anti-viral pathway responses to ssRNA viral infection. |
| format | Article |
| id | doaj-art-0d796ec2f0d34234a000a9150a8ea7e6 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2009-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-0d796ec2f0d34234a000a9150a8ea7e62025-08-20T03:19:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-11-01411e807910.1371/journal.pone.0008079Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection.Ping LiuMuping LuBing TianKui LiRoberto P GarofaloDeborah PrusakThomas G WoodAllan R Brasier<h4>Unlabelled</h4>Single stranded RNA (ssRNA) virus infection activates the retinoic acid inducible gene I (RIG-I)- mitochondrial antiviral signaling (MAVS) complex, a complex that coordinates the host innate immune response via the NF-kappaB and IRF3 pathways. Recent work has shown that the IkappaB kinase (IKK)gamma scaffolding protein is the final common adapter protein required by RIG-I.MAVS to activate divergent rate-limiting kinases downstream controlling the NF-kappaB and IRF3 pathways. Previously we discovered a ubiquitous IKKgamma splice-variant, IKKgammaDelta, that exhibits distinct signaling properties.<h4>Methodology/principal findings</h4>We examined the regulation and function of IKKgamma splice forms in response to ssRNA virus infection, a condition that preferentially induces full length IKKgamma-WT mRNA expression. In IKKgammaDelta-expressing cells, we found increased viral translation and cytopathic effect compared to those expressing full length IKKgamma-WT. IKKgammaDelta fails to support viral-induced IRF3 activation in response to ssRNA infections; consequently type I IFN production and the induction of anti-viral interferon stimulated genes (ISGs) are significantly attenuated. By contrast, ectopic RIG-I.MAVS or TNFalpha-induced canonical NF-kappaB activation is preserved in IKKgammaDelta expressing cells. Increasing relative levels of IKKgamma-WT to IKKgammaDelta (while keeping total IKKgamma constant) results in increased type I IFN expression. Conversely, overexpressing IKKgammaDelta (in a background of constant IKKgamma-WT expression) shows IKKgammaDelta functions as a dominant-negative IRF3 signaling inhibitor. IKKgammaDelta binds both IKK-alpha and beta, but not TANK and IKKepsilon, indicating that exon 5 encodes an essential TANK binding domain. Finally, IKKgammaDelta displaces IKKgammaWT from MAVS explaining its domainant negative effect.<h4>Conclusions/significance</h4>Relative endogenous IKKgammaDelta expression affects cellular selection of inflammatory/anti-viral pathway responses to ssRNA viral infection.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0008079&type=printable |
| spellingShingle | Ping Liu Muping Lu Bing Tian Kui Li Roberto P Garofalo Deborah Prusak Thomas G Wood Allan R Brasier Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection. PLoS ONE |
| title | Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection. |
| title_full | Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection. |
| title_fullStr | Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection. |
| title_full_unstemmed | Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection. |
| title_short | Expression of an IKKgamma splice variant determines IRF3 and canonical NF-kappaB pathway utilization in ssRNA virus infection. |
| title_sort | expression of an ikkgamma splice variant determines irf3 and canonical nf kappab pathway utilization in ssrna virus infection |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0008079&type=printable |
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