African swine fever virus pA104R protein acts as a suppressor of type I interferon signaling

Abstract

This study evaluates the role of the late viral protein, pA104R, in African swine fever virus immunosuppression. ASFV-encoded pA104R is a putative histone-like protein that is highly conserved throughout different virulent and non-virulent isolates. Previous studies have demonstrated that pA104R plays a vital role in the ASFV replication cycle and is a potential target for antiviral therapy. Here, we demonstrated that pA104R is a potent antagonist of type I interferon signaling. IFN-stimulated response element activity and subsequent transcription of co-transfected and endogenous interferon-stimulated genes were attenuated by pA104R treatment in HEK-293 T cells. Immunoprecipitation assay and reciprocal pull-down showed that pA104R does not interact directly with STAT1, STAT2, or IRF9. However, pA104R could inhibit IFN signaling by attenuating STAT1 phosphorylation, and we identified the critical amino acid residues (R/H69,72 and K/R92,94,97) involved through the targeted mutation functional assays. Although pA104R is a histone-like protein localized to the nucleus, it did not inhibit IFN signaling through its DNA-binding capacity. In addition, activation of the ISRE promoter by IRF9-Stat2(TA), a STAT1-independent pathway, was inhibited by pA104R. Further results revealed that both the transcriptional activation and recruitment of transcriptional stimulators by interferon-stimulated gene factor 3 were not impaired. Although we failed to determine a mechanism for pA104R-mediated IFN signaling inhibition other than attenuating the phosphorylation of STAT1, these results might imply a possible involvement of epigenetic modification by ASFV pA104R. Taken together, these findings support that pA104R is an antagonist of type I interferon signaling, which may interfere with multiple signaling pathways.

Characterization of the monoclonal antibody and the immunodominant B-cell epitope of African swine fever virus pA104R by using mouse model

“…In our previous investigation, we identified that pA104R possesses the ability to counteract the host’s innate immune response ( 40 ), thereby impacting its effectiveness as an immunological vaccine. Characterizing the immunodominant epitope of pA104R offers a means to overcome its inhibitory functional sites, enabling the full exploitation of its immunoprotective potential.…”

When ASFV Infection Meets the cGAS-STING Signaling Pathway

“…Meanwhile, Deletion B125R [160], C84L [161], L11L/L7L [162], DP71L [163], DP96R [163], B119L [164], and DP148R [163] significantly reduced the virulence of the virus and showed partial or complete protection against infection with ASFV strains. Besides, a lot of conserved B cell linear epitope in pB602L [165], p34 [166], p30 [167], pA104R [168], and p72 [169] have been identified. About the ASFV vaccine: (1) we can screen the optimal deletion combination of virulence genes (B125R, C84L, L11L/L7L, DP71L, DP96R, B119L, and DP148R) to obtain attenuated and attenuated vaccines; (2) we can concatenate mRNA vaccines that express different immunogenic proteins (p34, p72, p54, p30, and CD2v); and (3) we can also tandem mRNA vaccines that express different B cell linear epitopes (pB602L, p34, p30, pA104R, and p72) of the same immunogenic protein.…”

African Swine Fever Virus pF778R Attenuates Type I Interferon Response by Impeding STAT1 Nuclear Translocation

“…MGF360–9 L interacts with and degrades STAT1 and STAT2 via the apoptosis and proteasome pathways ( Zhang et al., 2022b ). pS273R and pA104R lead to the degradation of STAT2 and attenuation of STAT1 phosphorylation, respectively ( Chen et al., 2023 ; Li et al., 2023 ). pI215L triggers the degradation of IRF9 and STAT2 through autophagy-lysosome and proteasome pathways, respectively ( Li et al., 2022 ; Riera et al., 2022 ).…”