African Swine Fever Virus MGF360-14L Negatively Regulates Type I Interferon Signaling by Targeting IRF3.

Yang Wang,Hong Jia,Hongfei Zhu,Yajun Jiang,Ting Xin,Hainan Yu,Shuai Cui,Xiaoyu Guo,Yitong Jiang,Xixi Wang,Shiyu Chen,Xintao Gao

doi:10.3389/fcimb.2021.818969

Abstract

African swine fever (ASF) is a devastating infectious disease caused by African swine fever virus (ASFV). The ASFV genome encodes multiple structural and non-structural proteins that contribute to evasion of host immunity. In this study, we determined that the viral non-structural protein MGF360-14L inhibits interferon-β (IFN-β) promoter activity induced by cGAS-STING signaling. MGF360-14L was also found to downregulate expression of the IRF3 protein and promote its degradation through ubiquitin-meditated proteolysis. Moreover, MGF360-14L was shown to interact with and destabilize IRF3 by facilitating E3 ligase TRIM21-mediated K63-linked ubiquitination of IRF3. Overall, our study revealed that MGF360-14L promotes degradation of IRF3 through TRIM21, thereby inhibiting type I interferon production. These findings provide new insights into the mechanisms underlying ASFV immune evasion.

Highlights

African swine fever (ASF) is a deadly infectious disease caused by the African swine fever virus (ASFV)
Our study revealed that MGF360-14L promotes degradation of IFN regulatory factor 3 (IRF3) through tripartite motif protein 21 (TRIM21), thereby inhibiting type I interferon production
To determine whether MGF360-14L can inhibit the activity of type I IFN, MGF360-14L was cotransfected with cGAS-HA, stimulator of interferon gene (STING)-HA, and the IFN-b-luc promoter and subjected to dual-luciferase reporter assays to detect IFN-b promoter activity in HEK293T cells

Summary

Introduction

African swine fever (ASF) is a deadly infectious disease caused by the African swine fever virus (ASFV). ASFV is a large and complex icosahedral DNA virus that contains approximately 180∼190 kilobase pairs encoding more than 150 open reading frames (ORFs) (Alonso et al, 2018). Different strains of ASFV can cause different clinical manifestations, ranging from subclinical infection to death (Tulman et al, 2009). The main clinical signs observed in domestic pigs infected by virulent strains of ASFV include fever, hemorrhage, ataxia, and severe depression (Ge et al, 2018). As there is no commercial vaccine available, prevention and control of ASF are mainly accomplished through enhancing biosafety control or culling of infected animals (Karger et al, 2019). Safety of the attenuated vaccine has been challenged, and further evaluation is needed

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