SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways.
Viral infection or TLR3 engagement causes activation of the transcription factors IRF-3 and NF-kappaB, which collaborate to induce transcription of type I IFN genes. IKKepsilon and TBK1 are two IKK-related kinases critically involved in virus- and TLR3-triggered activation of IRF-3. We identified a protein termed SIKE (for Suppressor of IKKepsilon) that interacts with IKKepsilon and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Overexpression of SIKE disrupted the interactions of IKKepsilon or TBK1 with TRIF, RIG-I and IRF-3, components in virus- and TLR3-triggered IRF-3 activation pathways, but did not disrupt the interactions of TRIF with TRAF6 and RIP, components in TLR3-triggered NF-kappaB activation pathway. Consistently, overexpression of SIKE inhibited virus- and TLR3-triggered interferon-stimulated response elements (ISRE) but not NF-kappaB activation. Knockdown of SIKE potentiated virus- and TLR3-triggered ISRE but not NF-kappaB activation. Moreover, overexpression of SIKE inhibited IKKepsilon- and TBK1-mediated antiviral response. These findings suggest that SIKE is a physiological suppressor of IKKepsilon and TBK1 and plays an inhibitory role in virus- and TLR3-triggered IRF-3 but not NF-kappaB activation pathways.
Huang
Jun
J
College of Life Sciences, Peking University, Beijing, China.
Liu
Ting
T
Xu
Liang-Guo
LG
Chen
Danying
D
Zhai
Zhonghe
Z
Shu
Hong-Bing
HB
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D014645:Herpesvirus 3, Human / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism* / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000378:metabolism; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000502:physiology
D033942:Adaptor Proteins, Vesicular Transport; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C437968:PLAAT4 protein, human; D047428:Protein Kinase Inhibitors; D018168:Receptors, Retinoic Acid; C506822:SIKE protein, mouse; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; D011070:Poly I-C