The host defense against viral infection involves the recognition of pathogen-associated molecular patterns by a set of host pattern- recognition receptors1–3. Following viral infection, viral RNA in the endosome is recognized by membrane-bound Toll-like recep-

397 The host defense against viral infection involves the recognition of pathogen-associated molecular patterns by a set of host patternrecognition receptors1–3. Following viral infection, viral RNA in the endosome is recognized by membrane-bound Toll-like receptors (TLRs), and cytoplasmic viral double-stranded RNA is sensed by RNA helicase RIG-I–like receptors (RLRs). In addition, a small number of sensors of viral DNA have been identified, including DAI, IFI16, DDX41, MRE11 and cGAS4. Stimulation of these sensors triggers a series of signaling events to activate the transcription factors NF-κB, IRF3 or IRF7 and leads to the subsequent induction of type I interferons1–4. Insufficient interferon production causes chronic infection, whereas excessive interferon causes autoimmune and/or inflammatory diseases5–7. Therefore, balanced production of interferons is proposed as having a key role in the pathogenesis of autoimmune diseases as well as protective immune responses to viruses5–7. Much progress has been made in characterizing viral nucleic acid–triggered signaling pathways that result in the transcriptional activation of genes encoding type I interferons. After recognition of viral RNA through the RNA helicase domain (RLD), RLRs (including RIG-I and MDA5) interact with the signaling adaptor MAVS (also known as IPS-1, Cardif or VISA)1–3. MAVS further recruits the signaling adaptor TRAF3 and leads to Lys63 (K63)-linked ubiquitination of TRAF3, which subsequently interacts with a complex containing the kinases TBK1 and IKKε to activate the promoter of the gene encoding interferon-β (IFN-β)8–10. The stimulation of TLRs by viral nucleic acids leads to recruitment of the signaling adaptor TRIF (TICAM1) to induce IFN-β expression. The association of TRIF with TRAF3 and TBK1 triggers the activation of multiple intracellular cascades to induce IFN-β expression1. TRAF3 belongs to the TRAF family of ring-finger ubiquitin E3 ligases and is a versatile immunoregulator that undertakes its multiple functions in highly receptorand cell type–dependent manner10,11. Gene-ablation studies have demonstrated that TRAF3 is essential in the virus-triggered induction of IFN-β12,13. Increasing evidence suggests that the ubiquitination and de-ubiquitination of TRAF3 regulate the virus-triggered IFN-β-induction pathways. It has been shown that the tyrosine phosphatase PTPN22 and cellular apoptosis inhibitors cIAP1 and cIAP2 promote K63-linked ubiquitination of TRAF3 and regulate virus-triggered induction of type I interferons14,15. In contrast, the ubiquitin-modifying enzyme DUBA and ubiquitinbinding proteins HSCARG (NMRAL1), OTUB1/2 and UCHL1 have been shown to negatively regulate virus-induced interferon production through inhibiting the K63-linked ubiquitination of TRAF3, which is important for the recruitment of TBK1 (refs. 16–19). In addition, Triad3A, an E3 ubiquitin-protein ligase, negatively regulates the RIG-I RNA-sensing pathway through K48-linked-ubiquitin-mediated degradation of TRAF3 (ref. 20). However, whether and how additional molecules mediate other types of post-translational modifications of TRAF3 is unknown. Members of the CK1 family are evolutionary highly conserved and ubiquitously expressed serine-threonine–specific kinases that comprise six isoforms (CK1α, CK1δ, CK1ε and CK1γ1–CK1γ3) in vertebrates, which are highly conserved within their kinase domains but differ substantially in their amino acid sequence and length of their aminoand carboxy-terminal domains21,22. CK1 kinases