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

Date Published: March 28, 2013

Publisher: Public Library of Science

Author(s): Juliet Morrison, Maudry Laurent-Rolle, Ana M. Maestre, Ricardo Rajsbaum, Giuseppe Pisanelli, Viviana Simon, Lubbertus C. F. Mulder, Ana Fernandez-Sesma, Adolfo García-Sastre, Michael S. Diamond.

http://doi.org/10.1371/journal.ppat.1003265

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.

Partial Text

Approximately fifty million dengue virus (DENV) infections occur annually with more than forty percent of the human population at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). DF and its more severe form, DHF, are potentially fatal diseases caused by the four serotypes (1, 2, 3 and 4) of DENV [1]. As no approved vaccines or antiviral therapeutics are available for the prevention or treatment of DENV infections, it is imperative that the biology and immunology of DENV infections are better understood. An in depth comprehension of DENV-host interactions will accelerate our progress in developing DENV therapeutics.

The IFN-I response is one of the first lines of protection against DENV infection, and serves to curb viral replication and dissemination by generating an antiviral intracellular environment [48]. The potency of the type I IFN pathway is exemplified by the fact that DENV antagonizes both IFN synthesis and IFN signaling in order to ensure its replication and survival [13], [14], [33], [34], [35], [36], [37], [38]. DENV NS5 inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation, and STAT2 degradation promotes DENV replication [13], [14], [44]. With this study, we report the discovery of a host factor, UBR4, that is essential for DENV-dependent STAT2 degradation. We describe the interaction of UBR4 with NS5 and show that this interaction is crucial for inhibiting type-I IFN signaling and promoting efficient DENV replication.

 

Source:

http://doi.org/10.1371/journal.ppat.1003265

 

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