Editors' ChoiceVirology

ERK and the Viral Species Barrier

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Science's STKE  30 Nov 2004:
Vol. 2004, Issue 261, pp. tw428
DOI: 10.1126/stke.2612004tw428

Poxviruses are generally restricted to a particular species (see Vilcek). Wang et al. show that extracellular signal-regulated kinase 1 and 2 (ERK1/2) are essential for preventing susceptibility of mouse cells to infection by the rabbit poxvirus myxoma virus. Treatment of primary mouse embryo fibroblasts (MEFs) with an inhibitor for the kinase that activates ERK (U0126) caused the MEFs to become susceptible to myxoma virus infection. Knockdown of ERK1/2 with antisense oligonucleotides or application of antibodies against type I interferons (IFN-α/β) also caused an increase in MEF myxoma virus replication. Furthermore, MEFs deficient in either the IFN receptor (IFNaR) or STAT1 (a transcription factor involved in antiviral responses) also caused an increase in myxoma virus replication. Thus, ERK signaling appeared to stimulate type I IFN production, which in turn activated STAT signaling to promote an antiviral state. Myxoma virus caused an increase in ERK1/2 phosphorylation, increased transcription of IFN-α and IFN-β, and secretion of type I IFNs; these responses were blocked by U0126. The expression of genes encoding type I IFNs involves activation of the transcription factor IRF3, and for those IFN-α subtypes that are expressed after a delay IRF7 is involved. Myxoma virus infection stimulated IRF3 phosphorylation and nuclear translocation and induced mRNA accumulation for IRF7 through a pathway blocked by U0126. The antiviral state also involves inhibition of translation through phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which was stimulated by myxoma virus infection and blocked by U0126. Surprisingly, this phosphorylation of eIF2α did not require protein kinase R (PKR); however, it did require STAT1. The requirement for STAT1 in myxoma virus protection was verified in mice, and Stat1−/− mice were highly susceptible to infection, dying within a few days. These results indicate that, in response to viral challenge, ERK participates in a pathway leading to IFN production that contributes to the establishment of the antiviral state through activation of STAT1 and inhibition of translation.

J. Vilcek. Why are rabbits uniquely sensitive to myxoma virus? Cherchez l'interferon! Nat. Immunol. 5, 1205-1206 (2004). [Online Journal]

F. Wang, Y. Ma, J. W. Barrett, X. Gao, J. Loh, E. Barton. H. W. Virgin IV, G. McFadden, Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. Nat. Immunol. 5, 1266-1274 (2004). [Online Journal]

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