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

Published on May 15, 2019in The EMBO Journal11.227
· DOI :10.15252/embj.201899475
Eun-Sook Park11
Estimated H-index: 11
(Konkuk University),
Young-Ho Byun14
Estimated H-index: 14
(Yonsei University)
+ 22 AuthorsKyun-Hwan Kim22
Estimated H-index: 22
(Konkuk University)
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.
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