Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response

Ricardo Rajsbaum Gorodezky, Gijs A. Versteeg, Sonja Schmid, Ana M. Maestre, Alan Belicha-Villanueva, Carles Martínez-Romero, Jenish R. Patel, Juliet Morrison, Giuseppe Pisanelli, Lisa Miorin, Maudry Laurent-Rolle, Hong M. Moulton, David A. Stein, Ana Fernandez-Sesma, Benjamin R. tenOever, Adolfo García-Sastre

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)880-895
Number of pages16
JournalImmunity
Volume40
Issue number6
DOIs
StatePublished - Jun 19 2014
Externally publishedYes

Fingerprint

Polyubiquitin
Ubiquitin-Protein Ligases
Interferons
Antiviral Agents
Phosphotransferases
Ubiquitin
gamma-Glutamyl Hydrolase
I-kappa B Kinase
Genes
Interferon Type I
Up-Regulation
Phosphorylation
Cytokines
Infection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response. / Rajsbaum Gorodezky, Ricardo; Versteeg, Gijs A.; Schmid, Sonja; Maestre, Ana M.; Belicha-Villanueva, Alan; Martínez-Romero, Carles; Patel, Jenish R.; Morrison, Juliet; Pisanelli, Giuseppe; Miorin, Lisa; Laurent-Rolle, Maudry; Moulton, Hong M.; Stein, David A.; Fernandez-Sesma, Ana; tenOever, Benjamin R.; García-Sastre, Adolfo.

In: Immunity, Vol. 40, No. 6, 19.06.2014, p. 880-895.

Research output: Contribution to journalArticle

Rajsbaum Gorodezky, R, Versteeg, GA, Schmid, S, Maestre, AM, Belicha-Villanueva, A, Martínez-Romero, C, Patel, JR, Morrison, J, Pisanelli, G, Miorin, L, Laurent-Rolle, M, Moulton, HM, Stein, DA, Fernandez-Sesma, A, tenOever, BR & García-Sastre, A 2014, 'Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response', Immunity, vol. 40, no. 6, pp. 880-895. https://doi.org/10.1016/j.immuni.2014.04.018
Rajsbaum Gorodezky, Ricardo ; Versteeg, Gijs A. ; Schmid, Sonja ; Maestre, Ana M. ; Belicha-Villanueva, Alan ; Martínez-Romero, Carles ; Patel, Jenish R. ; Morrison, Juliet ; Pisanelli, Giuseppe ; Miorin, Lisa ; Laurent-Rolle, Maudry ; Moulton, Hong M. ; Stein, David A. ; Fernandez-Sesma, Ana ; tenOever, Benjamin R. ; García-Sastre, Adolfo. / Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response. In: Immunity. 2014 ; Vol. 40, No. 6. pp. 880-895.
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abstract = "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.",
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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

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.

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