Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic virus, which can cause fatal infection in cattle, sheep and other domestic animals. Clinical manifestations of RVFV infection in humans include encephalitis and hemorrhagic fever, which can lead to a high fatality rate in severe patients. Due to the potential of causing pandemic transmission and the lack of clinically approved vaccines or antiviral drugs for human use, RVFV is listed as a priority pathogen by the World Health Organization (WHO). However, the mechanisms underlying the pathogenesis of RVFV infection remain unclear, hindering the development of antiviral drugs against RVFV.
On October 3, 2024, the research groups of professors PENG Ke Peng and CAO Sheng from Wuhan Institute of Virology, Chinese Academy of Sciences, published an article in Cell entitled “Rift Valley fever virus coordinates the assembly of a programmable E3-ligase to promote viral replication”. This study revealed the pathogenic mechanism by which the non-structural protein NSs of RVFV coordinates the assembly of a programmable E3 ligase, leading to systematic inhibition of antiviral immunity and enhanced viral pathogenesis. This report also provides a novel target for the development of antiviral drugs against RVFV.
In order to investigate the mechanisms underlying NSs filament formation and pathogenicity of RVFV infection, the researchers reconstructed the NSs filament in vitro and characterized the structural details of NSs filament using cryo-EM. Further studies revealed that the NSs filamentous oligomer associate with F-box protein 3 (FBXO3) forming a NSs-FBXO3 E3-ligase. The remodeled NSs-FBXO3 E3-ligase targets the transcription factor IIH (TFIIH) complex, through the NSs-P62 interaction, leading to degradation of the TFIIH-complex and transcriptional inhibition of host cells. Furthermore, the researchers demonstrated that the TFIIH complex degradation induced by NSs filamentous structure systematically inhibited the expression of genes associated with the antiviral IFN-I immune responses, significantly promoting viral replication. Using an RVFV-infected mouse model, the researchers showed that targeted degradation of host proteins mediated by filamentous FBXO3-NSs E3 ligase is critical for multi-organ damage and pathogenesis caused by viral infection in vivo. Disrupting the formation of the filamentous FBXO3-NSs E3 ligase reduces the mortality rate of RVFV infection by more than 90%.
This study revealed a pathogenic mechanism, in which the non-structural protein NSs of RVFV systematically inhibits the host antiviral immunity and enhances viral pathogenesis by hijacking and remodeling host ubiquitin-proteasome degradation machinery. This study further provides evidences for using the viral non-structural protein as a new target for developing antiviral drug.
Prof. PENG Ke and Prof. CAO Sheng are the co-corresponding authors of this paper. Ph.D. student LI Huiling, laboratory technician ZHANG Yulan and laboratory technician RAO Guibo are the co-first authors of the paper.
Article link: https://doi.org/10.1016/j.cell.2024.09.008
