Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling

Juliet Morrison, Maudry Laurent-Rolle, Ana M. Maestre, Ricardo Rajsbaum Gorodezky, Giuseppe Pisanelli, Viviana Simon, Lubbertus C F Mulder, Ana Fernandez-Sesma, Adolfo García-Sastre

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

An estimated 50 million dengue virus (DENV) infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I) signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation.

Original languageEnglish (US)
Article numbere1003265
JournalPLoS Pathogens
Volume9
Issue number3
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Interferon Type I
Dengue Virus
Severe Dengue
Immune Evasion
Dengue
Virus Diseases
Proteasome Endopeptidase Complex
Virus Replication
Antiviral Agents
Vaccines

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Morrison, J., Laurent-Rolle, M., Maestre, A. M., Rajsbaum Gorodezky, R., Pisanelli, G., Simon, V., ... García-Sastre, A. (2013). Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling. PLoS Pathogens, 9(3), [e1003265]. https://doi.org/10.1371/journal.ppat.1003265

Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling. / Morrison, Juliet; Laurent-Rolle, Maudry; Maestre, Ana M.; Rajsbaum Gorodezky, Ricardo; Pisanelli, Giuseppe; Simon, Viviana; Mulder, Lubbertus C F; Fernandez-Sesma, Ana; García-Sastre, Adolfo.

In: PLoS Pathogens, Vol. 9, No. 3, e1003265, 2013.

Research output: Contribution to journalArticle

Morrison, J, Laurent-Rolle, M, Maestre, AM, Rajsbaum Gorodezky, R, Pisanelli, G, Simon, V, Mulder, LCF, Fernandez-Sesma, A & García-Sastre, A 2013, 'Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling', PLoS Pathogens, vol. 9, no. 3, e1003265. https://doi.org/10.1371/journal.ppat.1003265
Morrison, Juliet ; Laurent-Rolle, Maudry ; Maestre, Ana M. ; Rajsbaum Gorodezky, Ricardo ; Pisanelli, Giuseppe ; Simon, Viviana ; Mulder, Lubbertus C F ; Fernandez-Sesma, Ana ; García-Sastre, Adolfo. / Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling. In: PLoS Pathogens. 2013 ; Vol. 9, No. 3.
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