African swine fever virus maintains de novo global cellular protein synthesis and inhibits stress granules formation via dephosphorylating eIF2

African swine fever virus (ASFV) has caused enormous economic losses since its first reported detection, and there is still no effective vaccines or drug treatment. During infection, viruses may employ various strategies, such as regulating the host endoplasmic reticulum stress/unfolded protein response or the formation of stress granules (SGs), to form an optimal environment for virus replication. However, how ASFV infection regulates host endoplasmic reticulum stress, eIF2 alpha-regulated protein synthesis, and the formation of SGs remains unclear. Here, we evaluated the activation of ER stress and its three downstream axes during ASFV infection and identified a powerful dephosphorylation of eIF2 alpha by ASFV ex vivo. This strong dephosphorylation property could maintain the efficiency of eIF2 alpha-mediated de novo global protein synthesis, thus ensuring efficient viral protein synthesis at early stage. In addition, the powerful dephosphorylation of eIF2 alpha by ASFV upon infection could also inhibit the formation of SGs induced by sodium arsenite. In addition, a specific eIF2 alpha dephosphorylation inhibitor, salubrinal, could partially counteract ASFV-mediated eIF2 alpha dephosphorylation and inhibit viral replication. Our results provide new insights into the areas of ASFV`s escape from host immunity and hijacking of the host protein translation system.