한빛사 논문
Eun-Sook Park1,2, Young Ho Byun3,4 , Soree Park1, Yo Han Jang3,4, Woo-Ry Han1, Juhee Won1, Kyung Cho Cho5, Doo Hyun Kim1, Ah Ram Lee1, Gu-Choul Shin1, Yong Kwang Park1, Hong Seok Kang1, Heewoo Sim1, Yea Na Ha1, Byeongjune Jae1, Ahyun Son3, Paul Kim3,4, Jieun Yu3, Hye-Min Lee3, Sun-Bin Kwon3, Kwang Pyo Kim5, Seung-Hyun Lee6, Yeong-Min Park7, Baik L Seong3,4,* & Kyun-Hwan Kim1,2,8,**
1 Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea
2 KU Open Innovation Center, Konkuk University, Seoul, Korea
3 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
4 Vaccine Translational Research Center, Yonsei University, Seoul, Korea
5 Department of Applied Chemistry, Kyung Hee University, Yongin, Korea
6 Department of Microbiology, School of Medicine, Konkuk University, Seoul, Korea
7 Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Seoul, Korea
8 Research Institute of Medical Science, Konkuk University, Seoul, Korea
*Corresponding author.
**Corresponding author.
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.
Keywords : 1918 pandemic; DDX3; influenza PB1-F2; type I interferon signaling
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