Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.

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 vaccine...

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Autores principales:	Juliet Morrison, Maudry Laurent-Rolle, Ana M Maestre, Ricardo Rajsbaum, Giuseppe Pisanelli, Viviana Simon, Lubbertus C F Mulder, Ana Fernandez-Sesma, Adolfo García-Sastre
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c2c13699c8a14e3d9f30cc12b62340bf
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spelling	oai:doaj.org-article:c2c13699c8a14e3d9f30cc12b62340bf2021-11-18T06:05:51ZDengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.1553-73661553-737410.1371/journal.ppat.1003265https://doaj.org/article/c2c13699c8a14e3d9f30cc12b62340bf2013-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23555265/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374An 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.Juliet MorrisonMaudry Laurent-RolleAna M MaestreRicardo RajsbaumGiuseppe PisanelliViviana SimonLubbertus C F MulderAna Fernandez-SesmaAdolfo García-SastrePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 3, p e1003265 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Juliet Morrison Maudry Laurent-Rolle Ana M Maestre Ricardo Rajsbaum Giuseppe Pisanelli Viviana Simon Lubbertus C F Mulder Ana Fernandez-Sesma Adolfo García-Sastre Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.
description	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.
format	article
author	Juliet Morrison Maudry Laurent-Rolle Ana M Maestre Ricardo Rajsbaum Giuseppe Pisanelli Viviana Simon Lubbertus C F Mulder Ana Fernandez-Sesma Adolfo García-Sastre
author_facet	Juliet Morrison Maudry Laurent-Rolle Ana M Maestre Ricardo Rajsbaum Giuseppe Pisanelli Viviana Simon Lubbertus C F Mulder Ana Fernandez-Sesma Adolfo García-Sastre
author_sort	Juliet Morrison
title	Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.
title_short	Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.
title_full	Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.
title_fullStr	Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.
title_full_unstemmed	Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.
title_sort	dengue virus co-opts ubr4 to degrade stat2 and antagonize type i interferon signaling.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/c2c13699c8a14e3d9f30cc12b62340bf
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Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.

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