The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKKβ and increasing the stability of IκBα

ABSTRACT

African swine fever (ASF) is a highly contagious, often fatal viral disease caused by African swine fever virus (ASFV), which imposes a substantial economic burden on the global pig industry. When screening for the virus replication-regulating genes in the left variable region of the ASFV genome, we observed a notable reduction in ASFV replication following the deletion of the MGF300-4L gene. However, the role of MGF300-4L in ASFV infection remains unexplored. In this study, we found that MGF300-4L could effectively inhibit the production of proinflammatory cytokines IL-1β and TNF-α, which are regulated by the NF-κB signaling pathway. Mechanistically, we demonstrated that MGF300-4L interacts with IKKβ and promotes its lysosomal degradation via the chaperone-mediated autophagy. Meanwhile, the interaction between MGF300-4L and IκBα competitively inhibits the binding of the E3 ligase β-TrCP to IκBα, thereby inhibiting the ubiquitination-dependent degradation of IκBα. Remarkably, although ASFV encodes other inhibitors of NF-κB, the MGF300-4L gene-deleted ASFV (Del4L) showed reduced virulence in pigs, indicating that MGF300-4L plays a critical role in ASFV pathogenicity. Importantly, the attenuation of Del4L was associated with a significant increase in the production of IL-1β and TNF-α early in the infection of pigs. Our findings provide insights into the functions of MGF300-4L in ASFV pathogenicity, suggesting that MGF300-4L could be a promising target for developing novel strategies and live attenuated vaccines against ASF.

KEYWORDS:

• African swine fever virus
• MGF300-4L
• IKKβ
• IκBα
• chaperone-mediated autophagy

Acknowledgments

We thank all the staff of BSL3 at the National African Swine Fever Para-Reference Laboratory for their support and assistance with ASFV infection in animal experiments.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The RNA sequence reads generated in this study have been deposited in the sequence read archive database under the accession number PRJNA970972 (BioProject). The complete genome sequence of the ASFV HLJ/18 strain used in this study can be accessed under the GenBank accession no. MK333180.1.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [grant numbers 32202774, 32072854, U20A2060, 32372983, and 32072855] and the Heilongjiang Provincial Natural Science Foundation of China [grant number TD2023C007].