RNF123 has an E3 ligase-independent function in RIG-I-like receptor-mediated antiviral signaling.
Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are cytoplasmic sensors crucial for recognizing different species of viral RNAs, which triggers the production of type I interferons (IFNs) and inflammatory cytokines. Here, we identify RING finger protein 123 (RNF123) as a negative regulator of RIG-I and MDA5. Overexpression of RNF123 inhibits IFN-β production triggered by Sendai virus (SeV) and encephalomyocarditis picornavirus (EMCV). Knockdown or knockout of endogenous RNF123 potentiates IFN-β production triggered by SeV and EMCV, but not by the sensor of DNA viruses cGAS RNF123 associates with RIG-I and MDA5 in both endogenous and exogenous cases in a viral infection-inducible manner. The SPRY and coiled-coil, but not the RING, domains of RNF123 are required for the inhibitory function. RNF123 interacts with the N-terminal CARD domains of RIG-I/MDA5 and competes with the downstream adaptor VISA/MAVS/IPS-1/Cardif for RIG-I/MDA5 CARD binding. These findings suggest that RNF123 functions as a novel inhibitor of innate antiviral signaling mediated by RIG-I and MDA5, a function that does not depend on its E3 ligase activity.
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Shuai
S
Wang
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Yong-Kang
YK
Yang
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Tao
T
Chen
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Heng
H
Zhang
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Wei-Wei
WW
Yang
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Sheng-Sheng
SS
Song
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Zhong-He
ZH
Zhai
Key Laboratory of Cell Proliferation and Differentiation of The Ministry of Education, School of Life Sciences, Peking University, Beijing, China dychen@pku.edu.cn.
Dan-Ying
0000-0002-2826-3449
DY
Chen
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D060467:Disease Resistance; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D054884:Host-Pathogen Interactions; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1 / Q000378:metabolism; D016899:Interferon-beta; D051379:Mice; D011485:Protein Binding; D012327:RNA Virus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D011971:Receptors, Immunologic; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D016899:Interferon-beta; C574376:RNF123 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D000072640:Interferon-Induced Helicase, IFIH1
IFN‐β; MDA5; RIG‐I; RNF123; innate immunity