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The Ret Finger Protein Inhibits Signaling Mediated by the Noncanonical and Canonical IB Kinase Family Members¹

Jikun Zha^*, Ke-Jun Han, Liang-Guo Xu, Wei He^*, Qianhe Zhou^*, Danying Chen^*, Zhonghe Zhai^* and Hong-Bing Shu^2,

^* Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China; Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206; and College of Life Sciences, Wuhan University, Wuhan, China

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 IB kinase (IKK) family members, IKK and TRAF family-associated NF-B 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 IKK-interacting proteins, we identified Ret finger protein (RFP) as an IKK-interacting protein. Coimmunoprecipitation experiments indicated that RFP interacted with IKK and TRAF family-associated NF-B activator-binding kinase-1 as well as the two canonical IKK family members, IKK and IKK. RFP inhibited activation of the IFN-stimulated response element and/or NF-B 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-B 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.

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The JI 2006 176: 699-700. [Full Text]