Respiratory syncytial virus limits alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) phosphorylation to maintain translation and viral replication.
The impact of respiratory syncytial virus (RSV) on morbidity and mortality is significant in that it causes bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and pneumonia in immunocompromised hosts. RSV activates protein kinase R (PKR), a cellular kinase relevant to limiting viral replication (Groskreutz, D. J., Monick, M. M., Powers, L. S., Yarovinsky, T. O., Look, D. C., and Hunninghake, G. W. (2006) J. Immunol. 176, 1733-1740). It is activated by autophosphorylation, likely triggered by a double-stranded RNA intermediate during replication of the virus. In most instances, ph-PKR targets the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) protein via phosphorylation, leading to an inhibition of translation of cellular and viral protein. However, we found that although ph-PKR increases in RSV infection, significant eIF2alpha phosphorylation is not observed, and inhibition of protein translation does not occur. RSV infection attenuates eIF2alpha phosphorylation by favoring phosphatase rather than kinase activity. Although PKR is activated, RSV sequesters PKR away from eIF2alpha by binding of the kinase to the RSV N protein. This occurs in conjunction with an increase in the association of the phosphatase, PP2A, with eIF2alpha following PKR activation. The result is limited phosphorylation of eIF2alpha and continued translation of cellular and viral proteins.
Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Roy J, Iowa City, IA 52242, USA. dayna-groskreutz@uiowa.edu
Dayna J
DJ
Groskreutz
Ellen C
EC
Babor
Martha M
MM
Monick
Steven M
SM
Varga
Gary W
GW
Hunninghake
D045744:Cell Line, Tumor; D004847:Epithelial Cells; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008954:Models, Biological; D010766:Phosphorylation; D011070:Poly I-C / Q000737:chemistry; D014176:Protein Biosynthesis; D012330:RNA, Double-Stranded / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D012136:Respiratory Syncytial Viruses / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014779:Virus Replication / Q000235:genetics*
D015852:Eukaryotic Initiation Factor-2; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011070:Poly I-C