Abstract
Ubiquitination is an essential mechanism in the control of antiviral immunity upon virus infection. Here, we identify a series of ubiquitination-modulating enzymes that are modulated by vesicular stomatitis virus (VSV). Notably, TRIM24 is down-regulated through direct transcriptional suppression induced by VSV-activated IRF3. Reducing or ablating TRIM24 compromises type I IFN (IFN-I) induction upon RNA virus infection and thus renders mice more sensitive to VSV infection. Mechanistically, VSV infection induces abundant TRIM24 translocation to mitochondria, where TRIM24 binds with TRAF3 and directly mediates K63-linked TRAF3 ubiquitination at K429/K436. This modification of TRAF3 enables its association with MAVS and TBK1, which consequently activates downstream antiviral signaling. Together, these findings establish TRIM24 as a critical positive regulator in controlling the activation of antiviral signaling and describe a previously unknown mechanism of TRIM24 function.
© 2020 Zhu et al.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence
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Animals
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Antiviral Agents / metabolism*
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Base Sequence
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Cell Nucleus / metabolism
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Down-Regulation
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HEK293 Cells
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Humans
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Immunity*
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Inflammation / genetics
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Interferon Type I / metabolism
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Lysine / metabolism*
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria / metabolism
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Models, Biological
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Nuclear Proteins / chemistry
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport
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RING Finger Domains
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Signal Transduction
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TNF Receptor-Associated Factor 3 / chemistry
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TNF Receptor-Associated Factor 3 / genetics
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TNF Receptor-Associated Factor 3 / metabolism*
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Transcription Factors / chemistry
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Ubiquitination*
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Vesicular stomatitis Indiana virus / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Antiviral Agents
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Interferon Type I
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Nuclear Proteins
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TNF Receptor-Associated Factor 3
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Transcription Factors
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transcriptional intermediary factor 1
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Protein Serine-Threonine Kinases
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Lysine