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

PLoS Pathogens

Viviana Simon¹  Ana M. Maestre¹  Giuseppe Pisanelli¹  Ana Fernandez-Sesma¹  Juliet Morrison¹  Maudry Laurent-Rolle²  Lubbertus C. F. Mulder²  Ricardo Rajsbaum²  Adolfo García-Sastre² 

[1] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America;Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America

关键词: 293T cells;    Dengue virus;    Viral replication;    Vero cells;    Interferons;    Dendritic cells;    Ligases;    Immunoprecipitation;   

DOI  :  10.1371/journal.ppat.1003265

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY