African swine fever virus pA151R inhibits stress granule formation and host protein synthesis by disrupting mRNA nuclear export

African swine fever (ASF), caused by African swine fever virus (ASFV), is a highly devastating animal disease that has inflicted severe damage on global pig industry. Stress granules (SGs), as membrane-less dynamic cytoplasmic assemblies induced by stress, play a crucial role in the host antiviral response by sequestering viral components and regulating antiviral signaling pathways to restrict viral replication. Previous studies have reported that ASFV infection suppresses SGs formation; however, the viral proteins involved in regulating host stress responses and the underlying molecular mechanisms remain poorly understood. In this study, we found that ASFV pA151R inhibits SGs formation through both eIF2α-dependent and eIF2α-independent pathways. Mechanistically, pA151R inhibits host mRNA nuclear translocation and protein synthesis, and this function is dependent on its nuclear localization signal (NLS). Additionally, pA151R downregulates nuclear transport factor 2 like export factor 1 (NXT1) expression by inhibiting its promoter activity, thereby disrupting host mRNA nuclear export and ultimately inhibiting SGs formation. To validate the regulatory role of pA151R in SGs formation and host protein synthesis, we generated an A151R-deficient ASFV strain (ASFV-△A151R). Infection with ASFV-△A151R exhibited reduced inhibition of SGs formation and host protein synthesis, along with decreased viral replication capacity. Taken together, our findings reveal an ASFV immune evasion strategy mediated by pA151R through the inhibition of SGs formation, and provide novel targets for the development of anti-ASFV prevention and control therapies.