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.
Bibliographical noteFunding Information:
We thank Dr. McCullers (St. Jude Children’s Research Hospital) for the recombinant PR8 (PB1-F2[-]) and PR8 PB1-F2 (1918) viruses. This study was supported by grants from Korea Healthcare Technology R&D Project by the Ministry of Health & Welfare‚ Republic of Korea (Grant Nos. A103001 and HI13C0826), by the National Research Foundation of Korea (NRF) (NRF-2016R1A5A2012284 and NRF-2017R1A2B3006335), and by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) (No. NRF-2018M3A9H4079358 and NRF-2018M3A9H4079486).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)