Nuclear localization of the Nipah virus W protein allows for inhibition of both virus- and Toll-like receptor 3-triggered signaling pathways

Megan L. Shaw, Washington B. Cardenas, Dmitriy Zamarin, Peter Palese, Christopher F. Basler

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

Abstract

The Nipah virus V and W proteins, which are encoded by the P gene via RNA editing, have a common N-tenminal domain but unique C-terminal domains. They localize to the cytoplasm and nucleus, respectively, and have both been shown to function as inhibitors of JAK/STAT signaling. Here we report that V and W proteins also block virus activation of the beta interferon (IFN-β) promoter and the IFN regulatory factor 3 (IRF3)-responsive IFN-stimulated gene 54 promoter. Surprisingly, only W protein shows strong inhibition of promoter activation in response to stimulation of Toll-like receptor 3 (TLR3) by extracellular double-stranded RNA. This activity is dependent on the nuclear localization of W protein. Within the unique C-terminal domain of W protein, we have identified a nuclear localization signal (NLS) that requires basic residues at positions 439, 440, and 442. This NLS is responsible for mediating the preferential interaction of W protein with karyopherin-α 3 and karyopherin-α 4. Nuclear localization of W protein therefore enables it to target both virus and TLR3 pathways, whereas the cytoplasmic V protein is restricted to inhibiting the virus pathway. We propose that this discrepancy is in part due to the V protein being less able to block signaling in response to the kinase, TBK-1, whereas both V and W can prevent promoter activation in response IKKε. We demonstrate that, when the TLR3 pathway is stimulated, the levels of phosphorylated IRF3 are reduced in the presence of W protein but not V protein, confirming the differential effects of these proteins and illustrating that W protein-mediated inhibition is due to a loss of active IRF3.

Original languageEnglish
Pages (from-to)6078-6088
Number of pages11
JournalJournal of Virology
Volume79
Issue number10
DOIs
StatePublished - May 2005

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