JMJD6 negatively regulates cytosolic RNA induced antiviral signaling by recruiting RNF5 to promote activated IRF3 K48 ubiquitination.

Abstract	The negative regulation of antiviral immune responses is essential for the host to maintain homeostasis. Jumonji domain-containing protein 6 (JMJD6) was previously identified with a number of functions during RNA virus infection. Upon viral RNA recognition, retinoic acid-inducible gene-I-like receptors (RLRs) physically interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type-I interferon (IFN-I) production. Here, JMJD6 was demonstrated to reduce type-I interferon (IFN-I) production in response to cytosolic poly (I:C) and RNA virus infections, including Sendai virus (SeV) and Vesicular stomatitis virus (VSV). Genetic inactivation of JMJD6 enhanced IFN-I production and impaired viral replication. Our unbiased proteomic screen demonstrated JMJD6 contributes to IRF3 K48 ubiquitination degradation in an RNF5-dependent manner. Mice with gene deletion of JMJD6 through piggyBac transposon-mediated gene transfer showed increased VSV-triggered IFN-I production and reduced susceptibility to the virus. These findings classify JMJD6 as a negative regulator of the host's innate immune responses to cytosolic viral RNA.
Authors	Wei Zhang, Qi Wang, Fan Yang, Zixiang Zhu, Yueyue Duan, Yang Yang, Weijun Cao, Keshan Zhang, Junwu Ma, Xiangtao Liu, Haixue Zheng
Journal	PLoS pathogens (PLoS Pathog) Vol. 17 Issue 3 Pg. e1009366 (03 2021) ISSN: 1553-7374 [Electronic] United States
PMID	33684176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antiviral Agents DNA-Binding Proteins Interferon Regulatory Factor-3 Irf3 protein, mouse Membrane Proteins RNA JMJD6 protein, human Jumonji Domain-Containing Histone Demethylases RNF5 protein, human RNF5 protein, mouse Ubiquitin-Protein Ligases
Topics	Animals Antiviral Agents (metabolism) DNA-Binding Proteins (metabolism) Humans Interferon Regulatory Factor-3 (metabolism) Jumonji Domain-Containing Histone Demethylases (metabolism) Membrane Proteins (metabolism) Mice Proteomics RNA (metabolism) Signal Transduction (physiology) Ubiquitin-Protein Ligases (metabolism) Ubiquitination

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