OAS1 suppresses African swine fever virus replication by recruiting TRIM21 to degrade viral major capsid protein

Abstract

ABSTRACT African swine fever (ASF) is a highly contagious lethal viral disease in pigs caused by the African swine fever virus (ASFV), which has greatly threatened Chinese animal health and the pork industry. Studies on host-virus interaction are essential for developing novel anti-ASFV strategies. The 2′, 5′-oligoadenylate synthetase gene 1 (OAS1) is a key interferon-stimulating gene (ISG) effector protein that promotes innate antiviral responses. This study provided evidence that OAS1 is significantly upregulated and inhibits ASFV infection. Overexpression of OAS1 can promote the activation of the JAK-STAT pathway and enhance phosphorylation of STAT1 and STAT2, thus promoting innate immune responses and host antiviral strategies. Additional mechanism studies showed that AT-enriched dsDNA in the ASFV genome was converted to dsRNA by RNA polymerase III. OAS1 is thus activated after sensing the dsRNA to produce OAS, which could activate the antiviral function of RNase L and further degrade virus-derived mRNA. Furthermore, OAS1 directly interacts with P72, recruiting TRIM21 to inhibit the replication of ASFV and the assembly of mature virions using K63 as the main ubiquitin site to form a polyubiquitination chain to degrade P72. Furthermore, P72 can prevent the interaction between DDX6 and OAS1, inhibiting the production of avSG and the antiviral ability of the host. Our study identified a novel role of OAS1 by interacting with viral proteins P72 and affecting avSG formation inducing the host antiviral response, and controlling ASFV replication. IMPORTANCE African swine fever virus (ASFV) completes the replication process by resisting host antiviral response via inhibiting interferon (IFN) secretion and interferon-stimulated genes (ISGs) function. 2′, 5′-Oligoadenylate synthetase gene 1 (OAS1) has been reported to inhibit the replication of various RNA and some DNA viruses. However, the regulatory mechanisms involved in the ASFV-induced IFN-related pathway still need to be fully elucidated. Here, we found that OAS1, as a critical host factor, inhibits ASFV replication in an RNaseL-dependent manner. Furthermore, overexpression of OAS1 can promote the activation of the JAK-STAT pathway promoting innate immune responses. In addition, OAS1 plays a new function, which could interact with ASFV P72 protein to suppress ASFV infection. Mechanistically, OAS1 enhances the proteasomal degradation of P72 by promoting TRIM21-mediated ubiquitination. Meanwhile, P72 inhibits the production of avSG and affects the interaction between OAS1 and DDX6. Our findings demonstrated OAS1 as an important target against ASFV replication and revealed the mechanisms and intrinsic regulatory relationships during ASFV infection.