I226R Protein of African Swine Fever Virus Is a Suppressor of Innate Antiviral Responses

Abstract

African swine fever is one of the most devastating swine diseases caused by African swine fever virus (ASFV). Although ASFV encodes more than 160 viral proteins, the implication of a majority of ASFV proteins in regulating host immunity is yet to be explored, and the mechanisms of immune evasion by ASFV proteins are largely unknown. Here, we report that the I226R protein of ASFV significantly suppressed innate immune responses. The ectopic expression of ASFV I226R in 293T cells significantly inhibited the activation of interferon-stimulated response element promoters triggered by Sendai virus (SeV), poly(I:C), or cyclic GMP-AMP synthase (cGAS)/STING. The I226R protein caused a significant decrease in the expression of interferons and interferon-stimulating genes in cells infected with SeV. Similar results were obtained from experiments using I226R-overexpressed PK15 and 3D4/21 cells stimulated with vesicular stomatitis virus. We observed that I226R inhibited the activation of both nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). Furthermore, it was shown that overexpression of I226R suppressed IRF3 activation and caused the degradation of NF-κB essential modulator (NEMO) protein. The I226R-induced NEMO degradation could be prevented by treatment with MG132, a proteasome inhibitor. Together, these results reveal that the ASFV I226R protein impairs antiviral responses, likely through multiple mechanisms including the suppression of NF-κB and IRF3 activation, to counteract innate immune responses during the viral infection.

African Swine Fever Virus Structural Protein p17 Inhibits cGAS-STING Signaling Pathway Through Interacting With STING

“…A137R, D345L, DP96R, I215L, S273R, MGF-505-7R and MGF360 could inhibit DNA sensing cGAS-STING pathway by targeting TBK1 or IKK kinase activity (12, 25, 32-34, 36, 39). I226R, MGF-505-7R and MGF360-14L negatively regulate cGAS-STING pathway by targeting IRF3 (35,37,39). MGF-505-7R and MGF505-11R could suppress the cGAS-STING pathway by interacting with STING (38,39).…”

“…Recently, an increasing number of studies have suggested that several proteins encoded by ASFV including A137R (32), D345L (33), DP96R (34), I215L (12), I226R (35), UBCv1 (15), S273R (25), MGF360-11L (36), MGF360-14L (37), MGF505-11R (38) and MGF-505-7R (39) have the ability to inhibit the cGAS-STING signaling pathway through different mechanisms. A137R, D345L, DP96R, I215L, S273R, MGF-505-7R and MGF360 could inhibit DNA sensing cGAS-STING pathway by targeting TBK1 or IKK kinase activity (12, 25, 32-34, 36, 39).…”

Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning Pharmacodynamics and Pharmacokinetic Properties

“…Apigenin is effective against HSV-1, poliovirus type 2, HCV adenoviruses and hepatitis [192]. African swine fever virus (ASFV) production is decreased by 3 log due to apigenin's suppression of viral protein synthesis [193,194]. According to Shibata et al [195], apigenin prevents HCV replication by lowering microRNA122 which is unique to the liver.…”

Modulation of Host Antiviral Innate Immunity by African Swine Fever Virus: A Review

“…I226R can impair antiviral responses through the suppression of NF-κB and IRF3 activation. An ASFV mutant with the deleted I226R gene is dramatically attenuated and able to protect the pigs from death due to challenge with a homologous virus [ 55 , 56 ].…”