Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase.
Viral infection leads to activation of the transcription factors interferon regulatory factor-3 and NF-kappaB, 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-beta induction. Overexpression of DAK also inhibited cytoplasmic dsRNA and SeV-induced activation of the IFN-beta promoter, whereas knockdown of endogenous DAK by RNAi activated the IFN-beta promoter, and increased cytoplasmic dsRNA- or SeV-triggered activation of the IFN-beta 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.
Diao
Feici
F
College of Life Sciences, Peking University, Beijing 100871, China.
Li
Shu
S
Tian
Yang
Y
Zhang
Min
M
Xu
Liang-Guo
LG
Zhang
Yan
Y
Wang
Rui-Peng
RP
Chen
Danying
D
Zhai
Zhonghe
Z
Zhong
Bo
B
Tien
Po
P
Shu
Hong-Bing
HB
D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000821:virology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology; D038301:Virus Inactivation
D011971:Receptors, Immunologic; D017853:Phosphotransferases (Alcohol Group Acceptor); C023132:glycerone kinase; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1