E3 ubiquitin ligases are important in both innate and adaptive immunity. Here we report that Nrdp1, an E3 ubiquitin ligase, inhibited the production of proinflammatory cytokines but increased interferon-β production in Toll-like receptor–triggered macrophages by suppressing adaptor MyD88–dependent activation of transcription factors NF-κB and AP-1 while promoting activation of the kinase TBK1 and transcription factor IRF3. Nrdp1 directly bound and polyubiquitinated MyD88 and TBK1, which led to degradation of MyD88 and activation of TBK1. Knockdown of Nrdp1 inhibited the degradation of MyD88 and the activation of TBK1 and IRF3. Nrdp1-transgenic mice showed resistance to lipopolysaccharide-induced endotoxin shock and to infection with vesicular stomatitis virus. Our data suggest that Nrdp1 functions as both an adaptor protein and an E3 unbiquitin ligase to regulate TLR responses in different ways.
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We thank S. Akira (Research Institute for Microbial Diseases) for Myd88−/− mice; X. Yang (Beijing Institute of Biotechnology) for pIRES2-EGFP vector; Z.J. Chen (University of Texas Southwestern Medical Center) for TAK1 plasmid; T. Maniatis (Harvard University) for TBK1 and kinase-inactive TBK1 plasmids; S.J. Martin (Trinity College) for pGL3.5XêB-luciferase reporter plasmid; T Fujita (Tokyo Metropolitan Institute of Medical Science) for IRF3 reporter plasmids; Z. Wang for help in preparing Nrdp1-TG mice; H. An and W. Zhang for discussions; and Y. Li and M. Jin for technical assistance. Supported by the National Natural Science Foundation of China (30721091, 30572122 and 30771118), the Foundation for the Author of National Excellent Doctoral Dissertation of China (200775), the 973 National Key Basic Research Program of China (2007CB512403) and the Shanghai Committee of Science and Technology (06DJ14011 and 07QA14067).
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Wang, C., Chen, T., Zhang, J. et al. The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon. Nat Immunol 10, 744–752 (2009). https://doi.org/10.1038/ni.1742
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