TY - JOUR
T1 - Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response
AU - Rajsbaum, Ricardo
AU - Versteeg, Gijs A.
AU - Schmid, Sonja
AU - Maestre, Ana M.
AU - Belicha-Villanueva, Alan
AU - Martínez-Romero, Carles
AU - Patel, Jenish R.
AU - Morrison, Juliet
AU - Pisanelli, Giuseppe
AU - Miorin, Lisa
AU - Laurent-Rolle, Maudry
AU - Moulton, Hong M.
AU - Stein, David A.
AU - Fernandez-Sesma, Ana
AU - tenOever, Benjamin R.
AU - García-Sastre, Adolfo
N1 - Funding Information:
We thank R. Cadagan, O. Lizardo, and D. Bernal-Rubio for technical support. We thank C.F. Basler for kindly providing the IKKε deletion plasmids. Confocal microscopy was performed at the Mount Sinai Microscopy Shared Resource Facility. This work was supported in part by NIH R01AI080624 (B.R.T.), P01AI090935, U19 AI083025, U01AI095611, U19AI106754, and HHSN272201000054C (A.G.-S.), NIH/NIAID 1P01AI90935, 1R01AI073450, and DARPA HR0011-11-C-0094 (A.F.-S.), and by NIAID funded CEIRS (Center of Excellence in Influenza Research and Surveillance, contract # HHSN266200700010C) (A.G.-S. and A.F.-S.).
PY - 2014/6/19
Y1 - 2014/6/19
N2 - Type I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of hundreds ofIFN-I-stimulated genes (ISGs). The full breadth of ISG induction demands activation of a number of cellular factors including the IκB kinase epsilon (IKKε). However, the mechanism of IKKε 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 IKKε and promoted induction of IKKε-dependent ISGs. TRIM6 and the E2-ubiquitin conjugase UbE2K cooperated in the synthesis of unanchored K48-linked polyubiquitin chains, which activated IKKε 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.
AB - Type I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of hundreds ofIFN-I-stimulated genes (ISGs). The full breadth of ISG induction demands activation of a number of cellular factors including the IκB kinase epsilon (IKKε). However, the mechanism of IKKε 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 IKKε and promoted induction of IKKε-dependent ISGs. TRIM6 and the E2-ubiquitin conjugase UbE2K cooperated in the synthesis of unanchored K48-linked polyubiquitin chains, which activated IKKε 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.
UR - https://www.scopus.com/pages/publications/84903647409
UR - https://www.scopus.com/pages/publications/84903647409#tab=citedBy
U2 - 10.1016/j.immuni.2014.04.018
DO - 10.1016/j.immuni.2014.04.018
M3 - Article
C2 - 24882218
AN - SCOPUS:84903647409
SN - 1074-7613
VL - 40
SP - 880
EP - 895
JO - Immunity
JF - Immunity
IS - 6
ER -