Neutralizing innate host defenses to control viral translation in HSV-1 infected cells.
Lytic replication of many viruses activates an innate host response designed to prevent the completion of the viral lifecycle, thus impeding the spread of the infection. One branch of the host's complex reaction functions to incapacitate the cellular translational machinery on which the synthesis of viral polypeptides completely depends. This is achieved through the activation of specific protein kinases that phosphorylate eIF2 on its alpha subunit and inactivate this critical translation initiation factor. However, as continued synthesis of viral proteins is required to assemble the viral progeny necessary to transmit the infection to neighboring cells, viruses have developed a variety of strategies to counter this cellular response. Genetic and biochemical studies with herpes simplex virus type 1 (HSV-1) have revealed that the virus produces at least two discrete products at different times during its replicative program that act to prevent the accumulation of phosphorylated eIF2alpha. The gamma(1)34.5 gene product is expressed first, encoding a regulatory subunit that binds the cellular protein phosphatase 1alpha and regenerates pools of active eIF2 by removing the inhibitory phosphate from the alpha subunit. The second function, encoded by the product of the Us11 gene, specifies a double-stranded RNA-binding protein that prevents activation of PKR, a cellular eIF2alpha kinase. Together, both proteins cooperate to overcome the antiviral response of the host and properly regulate translation in HSV-1-infected cells.
Mohr
Ian
I
New York University School of Medicine, Department of Microbiology, MSB 214, New York, New York 10016, USA. ian.mohr@med.nyu.edu
D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006561:Herpes Simplex / Q000276:immunology* / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D008954:Models, Biological; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D014764:Viral Proteins; D019892:eIF-2 Kinase