Rajsbaum, R., Versteeg, G. A., Schmid, S., Maestre, A. M., Belicha-Villanueva, A., Martinez-Romero, C., Patel, J. R., Morrison, J., Pisanelli, G., Miorin, L., Laurent-Rolle, M., Moulton, H. M., Stein, D. A., Fernandez-Sesma, A., tenOever, B. R. and Garcia-Sastre, A.
Type I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of hundreds of IFN-I-stimulated genes (ISGs). The full breadth of ISG induction demands activation of a number of cellular factors including the IkappaB kinase epsilon (IKKepsilon). However, the mechanism of IKKepsilon activation upon IFN receptor signaling has remained elusive. Here we show that TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family of proteins, interacted with IKKepsilon and promoted induction of IKKepsilon-dependent ISGs. TRIM6 and the E2-ubiquitin conjugase UbE2K cooperated in the synthesis of unanchored K48-linked polyubiquitin chains, which activated IKKepsilon for subsequent STAT1 phosphorylation. Our work attributes a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response.