Abstract
Prolonged activation of interferon-STAT1 signaling is closely related to inflammatory autoimmune disorders, and therefore the identification of negative regulators of these pathways is important. Through high-content screening of 115 mouse RING-domain E3 ligases, we identified the E3 ubiquitin ligase RNF2 as a potent inhibitor of interferon-dependent antiviral responses. RNF2 deficiency substantially enhanced interferon-stimulated gene (ISG) expression and antiviral responses. Mechanistically, nuclear RNF2 directly bound to STAT1 after interferon stimulation and increased K33-linked polyubiquitination of the DNA-binding domain of STAT1 at position K379, in addition to promoting the disassociation of STAT1/STAT2 from DNA and consequently suppressing ISG transcription. Our study provides insight into the regulation of interferon-dependent responses via a previously unrecognized post-translational modification of STAT1 in the nucleus.
MeSH terms
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Animals
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Antiviral Agents / pharmacology
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Cell Line
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DNA / metabolism*
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Gene Expression / drug effects
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Interferon Type I / pharmacology*
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Lysine / genetics
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Lysine / metabolism*
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Macrophages / metabolism
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Macrophages / virology
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Polycomb Repressive Complex 1 / genetics
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Polycomb Repressive Complex 1 / metabolism*
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Protein Binding / drug effects
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism*
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STAT2 Transcription Factor / genetics
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STAT2 Transcription Factor / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination / drug effects
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Vesicular Stomatitis / genetics
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Vesicular Stomatitis / prevention & control
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Vesicular Stomatitis / virology
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Vesicular stomatitis Indiana virus / physiology
Substances
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Antiviral Agents
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Interferon Type I
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STAT1 Transcription Factor
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STAT2 Transcription Factor
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DNA
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Polycomb Repressive Complex 1
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Rnf2 protein, mouse
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Ubiquitin-Protein Ligases
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Lysine