Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction.
Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively ... suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner. Conversely, the genetic deletion or depletion of HOIL-1L and HOIP robustly enhances virus-induced type I IFN production. Taken together, the HOIL-1L/HOIP LUBAC specifically suppresses RIG-I ubiquitination and activation by inducing TRIM25 degradation and inhibiting TRIM25 interaction with RIG-I, resulting in the comprehensive suppression of the IFN-mediated antiviral signaling pathway.
Mesh Terms:
Animals, Carrier Proteins, Cells, Cultured, Humans, Interferon Type I, Mice, Mutation, Receptors, Retinoic Acid, Signal Transduction, Transcription Factors, Ubiquitin-Protein Ligases, Ubiquitination
Animals, Carrier Proteins, Cells, Cultured, Humans, Interferon Type I, Mice, Mutation, Receptors, Retinoic Acid, Signal Transduction, Transcription Factors, Ubiquitin-Protein Ligases, Ubiquitination
Mol. Cell
Date: Feb. 04, 2011
PubMed ID: 21292167
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