4 years ago

Nipah and Hendra Virus Nucleoproteins Inhibit Nuclear Accumulation of STAT1 and STAT2 by Interfering with Their Complex Formation.

Yoneda M, Kai C, Sato H, Takayama I, Sugai A
Henipaviruses, such as Nipah (NiV) and Hendra (HeV) viruses, are highly pathogenic zoonotic agents within the Paramyxoviridae family. The phosphoprotein (P) gene products of the paramyxoviruses have been well characterized in their interferon (IFN) antagonist activity and their contribution to viral pathogenicity. In this study, we demonstrated that the nucleoprotein (N) of henipaviruses also prevents the host IFN signaling pathway. Reporter assays demonstrated that NiV and HeV N proteins (NiV-N and HeV-N, respectively) suppressed both type-I and type-II IFN responses dose-dependently, and the inhibitory effect was mediated by their core-domains. Additionally, NiV-N prevented the nuclear transport of STAT1 and STAT2. However, NiV-N did not associate with Impα5, Impβ1, or Ran, which are members of the nuclear transport system for STATs. Although P protein is known as a binding partner of N protein and actively retains N protein in the cytoplasm, the IFN antagonist activity of N protein was not abolished by the co-expression of P protein. This suggests that the IFN inhibition by N protein occurs in the cytoplasm. Furthermore, we demonstrated that the complex formation of STATs was hampered in the N protein-expressing cells. As a result, STAT nuclear accumulation was reduced, causing a subsequent downregulation of ISGs (interferon-stimulated genes) due to low promoter occupancy by STAT complexes. This novel route for preventing host IFN responses by Henipavirus N proteins provides new insight for understanding the pathogenesis of these viruses.IMPORTANCE Paramyxoviruses are well known for suppressing interferon (IFN)-mediated innate immunity with their phosphoprotein (P) gene products, and the henipaviruses also possess P, V, W, and C proteins for evading host antiviral responses. There are numerous studies providing evidence for the relationship between viral pathogenicity and antagonistic activities against IFN responses by P gene products. Meanwhile, little attention has been paid to the influence of nucleoprotein (N) on host innate immune responses. In this study, we demonstrated that both NiV and HeV N proteins have an antagonistic activity against the JAK/STAT signaling pathway by preventing the nucleocytoplasmic trafficking of STAT1 and STAT2. This inhibitory effect was due to an impairment of their ability to form complexes. These results provide new insight into the involvement of N protein in viral pathogenicity via its IFN antagonism.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28835499

DOI: PubMed:28835499

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