title: Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.
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.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Juliet
authors.initials: J
authors.lastname: Morrison
authors.forename: Maudry
authors.initials: M
authors.lastname: Laurent-Rolle
authors.forename: Ana M
authors.initials: AM
authors.lastname: Maestre
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rajsbaum
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pisanelli
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.forename: Lubbertus C F
authors.initials: LC
authors.lastname: Mulder
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003716:Dengue Virus / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D007370:Interferon Type I / Q000378:metabolism*; D011485:Protein Binding; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000378:metabolism
chemical_list: D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D007370:Interferon Type I; C582223:NS5 protein, dengue virus; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D017361:Viral Nonstructural Proteins; C505833:UBR4 protein, human; D044767:Ubiquitin-Protein Ligases
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