Pseudosubstrate inhibition of protein kinase PKR by swine pox virus C8L gene product

The interferon-induced protein kinase PKR is activated upon binding double- stranded RNA and phosphorylates the translation initiation factor eIF2 alph a on Ser-51 to inhibit protein synthesis in virally infected cells. Swinepo x virus C8L and vaccinia virus K3L gene products structurally resemble the amino-terminal third of eIF2 alpha. We demonstrate that the C8L protein, li ke the K3L protein, can reverse the toxic effects caused by high level expr ession of human PKR in yeast cells. In addition, expression of either the K 3L or C8L gene product was found to reverse the inhibition of reporter gene translation caused by PKR expression in mammalian cells. The inhibitory fu nction of the K3L and C8L gene products in these assays was found to be cri tically dependent on residues near the carboxyl-termini of the proteins inc luding a sequence motif shared among eIF2 alpha and the C8L and K3L gene pr oducts. Thus, despite significant sequence differences both the C8L and K3L proteins function as pseudosubstrate inhibitors of PKR. (C) 2000 Academic Press.