Rift Valley Fever Virus NSs Protein Promotes Post-Transcriptional Downregulation of Protein Kinase PKR and Inhibits eIF2α Phosphorylation

PLoS Pathogens

Wataru Kamitani¹  Shinji Makino²  C. J. Peters²  Tetsuro Ikegami²  Krishna Narayanan³  Sungyong Won⁴ 

[1] Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America;Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America;Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America;Sealy Center for Vaccine Development, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America

关键词: Phosphorylation;    Rift Valley fever virus;    Viral replication;    Messenger RNA;    HEK 293 cells;    DNA transcription;    Protein translation;    Immunoprecipitation;   

DOI  :  10.1371/journal.ppat.1000287

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) is a negative-stranded RNA virus with a tripartite genome. RVFV is transmitted by mosquitoes and causes fever and severe hemorrhagic illness among humans, and fever and high rates of abortions in livestock. A nonstructural RVFV NSs protein inhibits the transcription of host mRNAs, including interferon-β mRNA, and is a major virulence factor. The present study explored a novel function of the RVFV NSs protein by testing the replication of RVFV lacking the NSs gene in the presence of actinomycin D (ActD) or α-amanitin, both of which served as a surrogate of the host mRNA synthesis suppression function of the NSs. In the presence of the host-transcriptional inhibitors, the replication of RVFV lacking the NSs protein, but not that carrying NSs, induced double-stranded RNA-dependent protein kinase (PKR)–mediated eukaryotic initiation factor (eIF)2α phosphorylation, leading to the suppression of host and viral protein translation. RVFV NSs promoted post-transcriptional downregulation of PKR early in the course of the infection and suppressed the phosphorylated eIF2α accumulation. These data suggested that a combination of RVFV replication and NSs-induced host transcriptional suppression induces PKR-mediated eIF2α phosphorylation, while the NSs facilitates efficient viral translation by downregulating PKR and inhibiting PKR-mediated eIF2α phosphorylation. Thus, the two distinct functions of the NSs, i.e., the suppression of host transcription, including that of type I interferon mRNAs, and the downregulation of PKR, work together to prevent host innate antiviral functions, allowing efficient replication and survival of RVFV in infected mammalian hosts.

【 授权许可】

CC BY