The Ret finger protein inhibits signaling mediated by the noncanonical and canonical IkappaB kinase family members.
IFN regulatory factor-3 is a transcription factor that is required for the rapid induction of type I IFNs in the innate antiviral response. Two noncanonical IkappaB kinase (IKK) family members, IKKepsilon and TRAF family-associated NF-kappaB activator-binding kinase-1, have been shown to phosphorylate IFN regulatory factor-3 and are critically involved in virus-triggered and TLR3-mediated signaling leading to induction of type I IFNs. In yeast two-hybrid screens for potential IKKepsilon-interacting proteins, we identified Ret finger protein (RFP) as an IKKepsilon-interacting protein. Coimmunoprecipitation experiments indicated that RFP interacted with IKKepsilon and TRAF family-associated NF-kappaB activator-binding kinase-1 as well as the two canonical IKK family members, IKKbeta and IKKalpha. RFP inhibited activation of the IFN-stimulated response element and/or NF-kappaB mediated by the IKK family members and triggered by TNF, IL-1, polyinosinic-polycytidylic acid (ligand for TLR3), and viral infection. Moreover, knockdown of RFP expression by RNA interference-enhanced activation of IFN-stimulated response element and/or NF-kappaB triggered by polyinosinic-polycytidylic acid, TNF, and IL-1. Taken together, our findings suggest that RFP negatively regulates signaling involved in the antiviral response and inflammation by targeting the IKKs.
Zha
Jikun
J
Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China;
Han
Ke-Jun
KJ
Xu
Liang-Guo
LG
He
Wei
W
Zhou
Qianhe
Q
Chen
Danying
D
Zhai
Zhonghe
Z
Shu
Hong-Bing
HB
D021581:Active Transport, Cell Nucleus; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D066298:In Vitro Techniques; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D029082:Sendai virus / Q000472:pathogenicity; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D000070584:Tripartite Motif Proteins
D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D009687:Nuclear Proteins; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins