This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In response to viral infection, the host attempts to limit virus production by inhibiting protein synthesis. At least two kinases can respond to limit viral infection; PKR and Perk. Both of these kinases inhibit protein synthesis by phosphorylating the translation initiation factor eIF2. eIF2 is a rate liming factor in the initiation of all protein synthesis. When phosphorylated, eIF2 cannot participate in the initiation of protein synthesis. This inhibition of protein synthesis can be localized within sub-cellular 'factories' or it can global in which case it culminates in apoptosis. Of these two enzymes, PKR is the best characterized; it is induced by a/b interferon and activated by double stranded RNA (dsRNA). dsRNA is produced during all viral infections and it both induces synthesis of PKR and activates Perk to phosphorylated eIF2. The fact that herpes, poxviruses, reoviruses, adenoviruses and delta hepatitis virus all encode different PKR inhibitors demonstrate the importance of PKR in the immune response. Perk is activated by unfolded or misfolded proteins in the endoplasmic reticulum. Many viruses produce misfolded protein during infection. In response to ER stress, Perk is activated, which phosphorylates eIF2 and inhibits protein synthesis either until the ER stress is relieved or apoptosis is induced. Here we report that that a neurovirulent strain herpes I, SP7 activates Perk and forms stress granules whereas an attenuated strain of HHV1, KOS, does not activate Perk and stress granules are not formed. This phenomenon may explain the pathogenic potential of these two strains of HHV1. We are currently investigating if the ICP 34.5 gene is responsible for this phenotype. We also report that the diabetes inducing EMCV (EMCV-D) significantly activates Perk as compared to the attenuated, non-diabetes inducing strain EMCV-B. Studies are undergoing to determine if Perk activation can be correlated with stress granule formation in EMCV.
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