Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-07, Vol.104 (28), p.11706-11711
• Main Authors: Diao, Feici, Li, Shu, Tian, Yang, Zhang, Min, Xu, Liang-Guo, Zhang, Yan, Wang, Rui-Peng, Chen, Danying, Zhai, Zhonghe, Zhong, Bo, Tien, Po, Shu, Hong-Bing
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antivirals; Biological Sciences; Cell Line; Cytoplasm - genetics; Cytoplasm - metabolism; Cytoplasm - virology; DEAD Box Protein 58; DEAD-box RNA Helicases - antagonists & inhibitors; DEAD-box RNA Helicases - physiology; Gene expression regulation; Humans; Immunity, Innate; Immunology; Infections; Interferon-Induced Helicase, IFIH1; Kinases; Mice; Phosphotransferases (Alcohol Group Acceptor) - physiology; Plasmids; Proteins; Receptors, Immunologic; Ribonucleic acid; RNA; Sendai virus - immunology; Signal Transduction - immunology; Transfection; Vesicular stomatitis Indiana virus - immunology; Viral infections; Viral RNA; Virus Inactivation; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0700544104

Viral infection leads to activation of the transcription factors interferon regulatory factor-3 and NF-κB, which collaborate to induce type I IFNs. The RNA helicase proteins RIG-I and MDA5 were recently identified as two cytoplasmic viral RNA sensors that recognize different species of viral RNAs produced during viral replication. In this study, we identified DAK, a functionally unknown dihydroacetone kinase, as a specific MDA5-interacting protein. DAK was associated with MDA5, but not RIG-I, under physiological conditions. Overexpression of DAK inhibited MDA5- but not RIG-I- or TLR3-mediated IFN-β induction. Overexpression of DAK also inhibited cytoplasmic dsRNA and SeV-induced activation of the IFN-β promoter, whereas knockdown of endogenous DAK by RNAi activated the IFN-β promoter, and increased cytoplasmic dsRNA- or SeV-triggered activation of the IFN-β promoter. In addition, overexpression of DAK inhibited MDA5- but not RIG-I-mediated antiviral activity, whereas DAK RNAi increased cytoplasmic dsRNA-triggered antiviral activity. These findings suggest that DAK is a physiological suppressor of MDA5 and specifically inhibits MDA5- but not RIG-I-mediated innate antiviral signaling.