The Ubiquitin Ligase TRIM56 Regulates Innate Immune Responses to Intracellular Double-Stranded DNA

The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cytosol and induces type I interferon (IFN) and other cytokines. Here, we identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon inducti...

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Published inImmunity (Cambridge, Mass.) Vol. 33; no. 5; pp. 765 - 776
Main Authors Tsuchida, Tetsuo, Zou, Jian, Saitoh, Tatsuya, Kumar, Himanshu, Abe, Takayuki, Matsuura, Yoshiharu, Kawai, Taro, Akira, Shizuo
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 24.11.2010
Elsevier Limited
Subjects
Cloning
Cytosol
Deoxyribonucleic acid
DNA
DNA - immunology
Gene expression
HEK293 Cells
HeLa Cells
Humans
Immune system
Immunity, Innate
Interferon-beta - immunology
Interferon-beta - metabolism
Kinases
Lysine - metabolism
Membrane Proteins - metabolism
Plasmids
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases - immunology
Protein-Serine-Threonine Kinases - metabolism
RNA polymerase
Rodents
Signal transduction
Tripartite Motif Proteins
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination - immunology
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Summary:The innate immune system detects pathogen- and host-derived double-stranded DNA exposed to the cytosol and induces type I interferon (IFN) and other cytokines. Here, we identified interferon-inducible tripartite-motif (TRIM) 56 as a regulator of double-stranded DNA-mediated type I interferon induction. TRIM56 overexpression enhanced IFN-β promoter activation after double-stranded DNA stimulation whereas TRIM56 knockdown abrogated it. TRIM56 interacted with STING and targeted it for lysine 63-linked ubiquitination. This modification induced STING dimerization, which was a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent induction of IFN-β. Taken together, these results indicate that TRIM56 is an interferon-inducible E3 ubiquitin ligase that modulates STING to confer double-stranded DNA-mediated innate immune responses. ► TRIM56 expression is induced by dsDNA and poly (I:C) stimulation ► TRIM56 enhanced IFN-β promoter activation after dsDNA stimulation ► TRIM56 promoted K63-linked ubiquitination and dimerization of STING ► These modifications are required to form a complex with TBK1 and induce IFN-β
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ISSN:1074-7613
1097-4180
1097-4180
DOI:10.1016/j.immuni.2010.10.013