Journal
JOURNAL OF IMMUNOLOGY
Volume 207, Issue 11, Pages 2754-2769Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.2100320
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Funding
- National Natural Science Foundation of China [31941002]
- Natural Science Foundation of Heilongjiang Province [YQ2020C022]
- State Key Laboratory of Veterinary Biotechnology Program [SKLVBP202101]
- major scientific research project of the Chinese Academy of Agricultural Sciences [CAAS-ZDXT2018007]
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African swine fever virus infection inhibits porcine alveolar macrophages' production of type I interferon and an ASFV gene, pI215L, acts as a strong inhibitor of type I interferon production independent of its E2 enzyme activity. The mechanism involves pI215L interacting with RNF138 to degrade RNF128, ultimately reducing K63-linked polyubiquitination of TANK-binding kinase 1 and type I interferon production.
African swine fever is a severe animal infectious disease caused by African swine fever virus (ASFV), and the morbidity and mortality associated with virulent ASFV isolates are as high as 100%. Previous studies showed that the ability of ASFV to antagonize IFN production is closely related to its pathogenicity. Here, we report that ASFV HLJ/18 infection induced low levels of type I IFN and inhibited cGMP-AMP-induced type I IFN production in porcine alveolar macrophages that were isolated from specific pathogen-free Landrace piglets. Subsequently, an unbiased screen was performed to screen the ASFV genes with inhibitory effects on the type I IFN production. ASFV pI215L, a viral E2 ubiquitin-conjugating enzyme, was identified as one of the strongest inhibitory effectors on the production of type I IFN. Knockdown of pI215L expression inhibited ASFV replication and enhanced IFN-beta production. However, inhibition of type I IFN production by pI215L was independent of its E2 enzyme activity. Furthermore, we found that pI215L inhibited type I IFN production and K63-linked polyubiquitination of TANK-binding kinase 1 through pI215L-binding RING finger protein 138 (RNF138). ASFV pI215L enhanced the interaction between RNF138 and RNF128 and promoted RNF138 to degrade RNF128, which resulted in reduced K63-linked polyubiquitination of TANK-binding kinase 1 and type I IFN production. Taken together, our findings reveal a novel immune escape mechanism of ASFV, which provides a clue to the design and development of an immune-sensitive attenuated live vaccine.
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