Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 6 min ago
Peer-reviewedCC BY 4.0Journal of Virology

Rift Valley fever virus virulence factor NSs targets ATF4- and XBP1-driven unfolded protein response

  • Kaori Terasaki1,2
  • Shinji Makino1,2,3,4,5
5 affiliations
  1. 1Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA
  2. 2Institute for Human Infection and Immunity, The University of Texas Medical Branch, Galveston, Texas, USA
  3. 3Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas, USA
  4. 4UTMB Center for Tropical Diseases, The University of Texas Medical Branch, Galveston, Texas, USA
  5. 5The Sealy Institute for Vaccine Sciences, The University of Texas Medical Branch, Galveston, Texas, USA
Read full textDOICite

Abstract

Rift Valley fever virus (RVFV) is a mosquito-borne arbovirus that infects humans and domestic ruminants, significantly impacting public health and the economy in African and Middle Eastern countries. RVFV non-structural protein NSs is a major viral virulence factor and possesses multiple functions to counteract host antiviral responses. One of its functions is to block host transcription by promoting degradation of subunits of the host transcription factor IIH (TFIIH). However, the biological significance of this function in the RVFV life cycle remains unclear. We used RVFV strain MP-12 and its mutant lacking the TFIIH degradation function (NSs-mut virus) to identify host genes targeted by NSs-mediated transcription suppression. We found that NSs-mut virus, but not MP-12, upregulated unfolded protein response (UPR) target genes compared to uninfected cells. Both viruses activated all three ER stress sensors, including PERK and IRE1. However, only MP-12 inhibited the PERK and IRE1 pathways by inhibiting the expression of their respective downstream mediators ATF4 and XBP1. ATF4 expression was inhibited at the transcriptional level, whereas XBP1 expression was inhibited at the post-transcriptional level. ATF4 depletion negatively impacted virus titer and the production of non-plaque-forming particles, resulting in alteration of the particle-to-PFU ratio of the viruses. We also showed that activation of the PERK pathway plays a pro-survival role in NSs-mut virus-infected cells, suggesting the involvement of the PERK pathway in RVFV-induced cytotoxicity. Taken together, our study revealed that RVFV NSs inhibits two out of the three UPR pathways and promotes RVFV-induced cytotoxicity by inhibiting the PERK pathway.

IMPORTANCE: The Rift Valley fever virus (RVFV) NSs protein is a major virulence factor with multiple functions, including inhibition of general host transcription. RVFV carrying a mutated NSs that lacks the transcription suppression function is less cytotoxic in vitro and less virulent in mice compared to its parental virus, suggesting that NSs-mediated host transcription suppression is important for RVFV virulence. Experiments using this mutant virus and its parental RVFV revealed that NSs inhibits the expression of unfolded protein response (UPR) mediators ATF4 and XBP1, which act downstream of the PERK and IRE1 pathways, respectively. Our data also showed that activation of PERK promotes cell survival in RVFV infection. These data suggest that the NSs-mediated inhibition of UPR pathways contributes to RVFV pathogenicity.

Related

  1. A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex
    Ivan Vlassakev, Christina Savva, Liying Zhou +5
    Cell ReportsPeer-reviewedCC BY 4.0Full textGeneral medicineCrossref
  2. BCAM-AKT2 fusion protein promotes unfolded protein response driven oncogenic signaling in SKOV3 epithelial ovarian cancer cell line
    Hala Khazem, Ravid Solomon Zemler, Liron Vardi David +5
    PLOS OnePeer-reviewedCC BY 4.0Full textMolecular biology & gene regulationStatisticsPLOS
  3. The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence
    Maria Jose Perez J., Alicia Lam, Christin Weissleder +11
    Nature NeurosciencePeer-reviewedCC BYFull text14 citedNeurologyOpenAlex
  4. Placental LBX1 dysregulation drives ribosomal dysfunction and unfolded protein response in spontaneous preterm birth
    A. Biswas, N. Kharbanda, K. S. Bisht +11
    medRxivPreprintCC BY-NC-NDFull textObstetrics, gynaecology & paediatricsmedRxiv
  5. β-cell NCK1 is reduced in type 2 diabetes, impairing the unfolded protein response and insulin secretion while revealing sex-specific adaptation
    L. Monteillet, N. Jouvet, R. Huet +10
    bioRxivPreprintCC BY-NC-NDFull textPhysiologybioRxiv

Cite

BibTeXRIS
BibTeX
@article{terasaki2026rift,
  title = {{Rift Valley fever virus virulence factor NSs targets ATF4- and XBP1-driven unfolded protein response}},
  author = {Kaori Terasaki and Shinji Makino},
  journal = {Journal of Virology},
  year = {2026},
  month = sep,
  doi = {10.1128/jvi.01233-26},
  url = {https://doi.org/10.1128/jvi.01233-26},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Rift Valley fever virus virulence factor NSs targets ATF4- and XBP1-driven unfolded protein response
AU  - Kaori Terasaki
AU  - Shinji Makino
PY  - 2026
DA  - 2026/09/24
JO  - Journal of Virology
DO  - 10.1128/jvi.01233-26
UR  - https://doi.org/10.1128/jvi.01233-26
AB  - Rift Valley fever virus (RVFV) is a mosquito-borne arbovirus that infects humans and domestic ruminants, significantly impacting public health and the economy in African and Middle Eastern countries. RVFV non-structural protein NSs is a major viral virulence factor and possesses multiple functions to counteract host antiviral responses. One of its functions is to block host transcription by promoting degradation of subunits of the host transcription factor IIH (TFIIH). However, the biological significance of this function in the RVFV life cycle remains unclear. We used RVFV strain MP-12 and its mutant lacking the TFIIH degradation function (NSs-mut virus) to identify host genes targeted by NSs-mediated transcription suppression. We found that NSs-mut virus, but not MP-12, upregulated unfolded protein response (UPR) target genes compared to uninfected cells. Both viruses activated all three ER stress sensors, including PERK and IRE1. However, only MP-12 inhibited the PERK and IRE1 pathways by inhibiting the expression of their respective downstream mediators ATF4 and XBP1. ATF4 expression was inhibited at the transcriptional level, whereas XBP1 expression was inhibited at the post-transcriptional level. ATF4 depletion negatively impacted virus titer and the production of non-plaque-forming particles, resulting in alteration of the particle-to-PFU ratio of the viruses. We also showed that activation of the PERK pathway plays a pro-survival role in NSs-mut virus-infected cells, suggesting the involvement of the PERK pathway in RVFV-induced cytotoxicity. Taken together, our study revealed that RVFV NSs inhibits two out of the three UPR pathways and promotes RVFV-induced cytotoxicity by inhibiting the PERK pathway.  IMPORTANCE: The Rift Valley fever virus (RVFV) NSs protein is a major virulence factor with multiple functions, including inhibition of general host transcription. RVFV carrying a mutated NSs that lacks the transcription suppression function is less cytotoxic in vitro and less virulent in mice compared to its parental virus, suggesting that NSs-mediated host transcription suppression is important for RVFV virulence. Experiments using this mutant virus and its parental RVFV revealed that NSs inhibits the expression of unfolded protein response (UPR) mediators ATF4 and XBP1, which act downstream of the PERK and IRE1 pathways, respectively. Our data also showed that activation of PERK promotes cell survival in RVFV infection. These data suggest that the NSs-mediated inhibition of UPR pathways contributes to RVFV pathogenicity.
SN  - 0022-538X
SN  - 1098-5514
ER  -