Diversity in viral anti-PKR mechanisms: a remarkable case of evolutionary convergence.

Abstract

Most viruses express during infection products that prevent or neutralize the effect of the host dsRNA activated protein kinase (PKR). Translation of Sindbis virus (SINV) mRNA escapes to PKR activation and eIF2 phosphorylation in infected cells by a mechanism that requires a stem loop structure in viral 26S mRNA termed DLP to initiate translation in the absence of functional eIF2. Unlike the rest of viruses tested, we found that Alphavirus infection allowed a strong PKR activation and eIF2α phosphorylation in vitro and in infected animals so that the presence of DLP structure in mRNA was critical for translation and replication of SINV. Interestingly, infection of MEFs with some viruses that express PKR inhibitors prevented eIF2α phosphorylation after superinfection with SINV, suggesting that viral anti-PKR mechanisms could be exchangeable. Thus, translation of SINV mutant lacking the DLP structure (ΔDLP) in 26S mRNA was partially rescued in cells expressing vaccinia virus (VV) E3 protein, a known inhibitor of PKR. This case of heterotypic complementation among evolutionary distant viruses confirmed experimentally a remarkable case of convergent evolution in viral anti-PKR mechanisms. Our data reinforce the critical role of PKR in regulating virus-host interaction and reveal the versatility of viruses to find different solutions to solve the same conflict.

• Authors: Elena Domingo-Gil, René Toribio, José Luis Nájera, Mariano Esteban, Iván Ventoso
• Journal: PloS one (PLoS One) Vol. 6 Issue 2 Pg. e16711 (Feb 02 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21311764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• eIF-2 Kinase

Topics

• Animals
• Base Sequence
• Cells, Cultured
• Evolution, Molecular
• Genetic Variation (physiology)
• Host-Pathogen Interactions (genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Biological
• Molecular Sequence Data
• Nucleic Acid Conformation
• Signal Transduction (genetics)
• Sindbis Virus (genetics, metabolism)
• Virus Replication (genetics)
• Viruses (genetics, metabolism, pathogenicity)
• eIF-2 Kinase (antagonists & inhibitors, genetics)