Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza

Eun Sook Park, Young Ho Byun, Soree Park, Yo Han Jang, Woo Ry Han, Juhee Won, Kyung Cho Cho, Doo Hyun Kim, Ah Ram Lee, Gu Choul Shin, Yong Kwang Park, Hong Seok Kang, Heewoo Sim, Yea Na Ha, Byeongjune Jae, Ahyun Son, Paul Kim, Jieun Yu, Hye Min Lee, Sun Bin KwonKwang Pyo Kim, Seung Hyun Lee, Yeong Min Park, Baik L. Seong, Kyun Hwan Kim

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The multifunctional influenza virus protein PB1-F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1-F2 protein not only interferes with the mitochondria-dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD-box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome-dependent degradation. Interactome analysis revealed that 1918 PB1-F2, but not PR8 PB1-F2, binds to DDX3 and causes its co-degradation. Consistent with intrinsic protein instability as basis for this gain-of-function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 PB1-F2 protein. Infusing mice with recombinant DDX3 protein completely rescued them from lethal infection with the 1918 PB1-F2-producing virus. Alongside NS1 protein, 1918 PB1-F2 therefore constitutes a potent IFN antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.

Original languageEnglish
Article numbere99475
JournalEMBO Journal
Volume38
Issue number10
DOIs
Publication statusPublished - 2019 May 15

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Park, E. S., Byun, Y. H., Park, S., Jang, Y. H., Han, W. R., Won, J., Cho, K. C., Kim, D. H., Lee, A. R., Shin, G. C., Park, Y. K., Kang, H. S., Sim, H., Ha, Y. N., Jae, B., Son, A., Kim, P., Yu, J., Lee, H. M., ... Kim, K. H. (2019). Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza. EMBO Journal, 38(10), [e99475]. https://doi.org/10.15252/embj.201899475