title: Mechanistic Insight into the Host Transcription Inhibition Function of Rift Valley Fever Virus NSs and Its Importance in Virulence.
abstract: Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, causes periodic outbreaks in livestocks and humans in countries of the African continent and Middle East. RVFV NSs protein, a nonstructural protein, is a major virulence factor that exhibits several important biological properties. These include suppression of general transcription, inhibition of IFN-β promoter induction and degradation of double-stranded RNA-dependent protein kinase R. Although each of these biological functions of NSs are considered important for countering the antiviral response in the host, the individual contributions of these functions towards RVFV virulence remains unclear. To examine this, we generated two RVFV MP-12 strain-derived mutant viruses. Each carried mutations in NSs that specifically targeted its general transcription inhibition function without affecting its ability to degrade PKR and inhibit IFN-β promoter induction, through its interaction with Sin3-associated protein 30, a part of the repressor complex at the IFN-β promoter. Using these mutant viruses, we have dissected the transcription inhibition function of NSs and examined its importance in RVFV virulence. Both NSs mutant viruses exhibited a differentially impaired ability to inhibit host transcription when compared with MP-12. It has been reported that NSs suppresses general transcription by interfering with the formation of the transcription factor IIH complex, through the degradation of the p62 subunit and sequestration of the p44 subunit. Our study results lead us to suggest that the ability of NSs to induce p62 degradation is the major contributor to its general transcription inhibition property, whereas its interaction with p44 may not play a significant role in this function. Importantly, RVFV MP-12-NSs mutant viruses with an impaired general transcription inhibition function showed a reduced cytotoxicity in cell culture and attenuated virulence in young mice, compared with its parental virus MP-12, highlighting the contribution of NSs-mediated general transcription inhibition towards RVFV virulence.
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Kaori
authors.initials: K
authors.lastname: Terasaki
authors.affiliation: Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Sydney I
authors.initials: SI
authors.lastname: Ramirez
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, United States of America.|Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas, United States of America.|UTMB Center for Tropical Diseases, The University of Texas Medical Branch, Galveston, Texas, United States of America.|Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas, United States of America.|The Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Shinji
authors.initials: S
authors.lastname: Makino
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000235:genetics; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D012295:Rift Valley Fever / Q000821:virology; D012296:Rift Valley fever virus / Q000235:genetics* / Q000472:pathogenicity*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; D016899:Interferon-beta