ICP34.5 Protein of Herpes Simplex Virus Facilitates the Initiation of Protein Translation by Bridging Eukaryotic Initiation Factor 2α (eIF2α) and Protein Phosphatase 1

The ICP34.5 protein of herpes simplex virus type 1 is a neurovirulence factor that plays critical roles in viral replication and anti-host responses. One of its functions is to recruit protein phosphatase 1 (PP1) that leads to the dephosphorylation of the alpha subunit of translation initiation factor eIF2 (eIF2 alpha), which is inactivated by infection-induced phosphorylation. As PP1 is a protein phosphatase with a wide range of substrates, the question remains to be answered how ICP34.5 directs PP1 to specifically dephosphorylate eIF2 alpha. Here we report that ICP34.5 not only binds PP1 but also associates with eIF2 alpha by in vitro and in vivo assays. The binding site of eIF2 alpha is identified at amino acids 233-248 of ICP34.5, which falls in the highly homologous region with human gene growth arrest and DNA damage 34. The interaction between ICP34.5 and eIF2 alpha is independent of the phosphorylation status of eIF2 alpha at serine 51. Deletion mutation of this region results in the failure of dephosphorylation of eIF2 alpha by PP1 and, consequently, interrupts viral protein synthesis and replication. Our data illustrated that the binding between viral protein ICP34.5 and the host eIF2 alpha is crucial for the specific dephosphorylation of eIF2 alpha by PP1. We propose that herpes simplex virus protein ICP34.5 bridges PP1 and eIF2 alpha via their binding motifs and thereby facilitates the protein synthesis and viral replication.