Abstract
Ubiquitination and deubiquitination have emerged as critical post-translational regulatory mechanisms for activation or attenuation of the virus-triggered type I interferon (IFN)(2) induction pathways. In this study, we identified two deubiquitinating enzymes, OTUB1 and OTUB2, as negative regulators of virus-triggered type I IFN induction. Overexpression of OTUB1 and OTUB2 inhibited virus-induced activation of IRF3 and NF-kappaB, transcription of the IFNB1 gene as well as cellular antiviral response, whereas knockdown of OTUB1 and OTUB2 had opposite effects. Coimmunoprecipitations indicated OTUB1 and -2 interacted with TRAF3 and TRAF6, two E3 ubiquitin ligases required for virus-triggered IRF3 and NF-kappaB activation, respectively. Furthermore, we found that OTUB1 and OTUB2 mediated virus-triggered deubiquitination of TRAF3 and -6. These findings suggest that OTUB1 and OTUB2 negatively regulate virus-triggered type I IFN induction and cellular antiviral response by deubiquitinating TRAF3 and -6.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism*
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Deubiquitinating Enzymes
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Humans
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Immunoblotting
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Immunoprecipitation
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Interferon Regulatory Factor-3 / metabolism
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Interferon Type I / metabolism
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NF-kappa B / metabolism
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Protein Binding
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Sendai virus / physiology*
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Signal Transduction / genetics
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Signal Transduction / physiology*
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TNF Receptor-Associated Factor 3 / genetics
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TNF Receptor-Associated Factor 3 / metabolism*
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism*
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Thiolester Hydrolases / genetics
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Thiolester Hydrolases / metabolism*
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Ubiquitination / genetics
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Ubiquitination / physiology
Substances
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Interferon Type I
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NF-kappa B
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TNF Receptor-Associated Factor 3
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TNF Receptor-Associated Factor 6
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OTUB2 protein, human
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Thiolester Hydrolases
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Deubiquitinating Enzymes
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OTUB1 protein, human
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Cysteine Endopeptidases