The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKK β and increasing the stability of I κ B α

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-1 β and TNF- α , which are regulated by the NF- κ B signaling pathway. Mechanistically, we demonstrated that MGF300-4L interacts with IKK β and promotes its lysosomal degradation via the chaperone-mediated autophagy. Meanwhile, the interaction between MGF300-4L and I κ B α competitively inhibits the binding of the E3 ligase β -TrCP to I κ B α , thereby inhibiting the ubiquitination-dependent degradation of I κ B α . Remarkably, although ASFV encodes other inhibitors of NF- κ B, 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-1 β 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.

Genetic Variations of African Swine Fever Virus: Major Challenges and Prospects

“…This peculiarity could be ascribed to the compensatory mechanisms inherent in the large ASFV genome, which may mitigate the effects of reducing protein functionality. Out of the many insertion and deletion events, the genes that had the most significant impact were multigene families ( MGFs ) and EP402R [ 36 , 37 , 38 ]. During the 2020 incursion into Germany, ASFV unexpectedly diverged into five distinctly different lineages, each exhibiting at least 10 unique variants characterized by previously unidentified high-impact mutations.…”

The MGF300-2R Protein of African Swine Fever Virus Promotes IKKβ Ubiquitination by Recruiting the E3 Ubiquitin Ligase TRIM21

“…The causative agent, African swine fever virus (ASFV), is a large, double-stranded DNA virus. The ASFV genome encodes 68 structural proteins and more than 100 non-structural proteins, with over 10 virulence factors discovered in the past five years, such as MGF300-2R, MGF300-4L, A137R, and H240R [ 2 , 4 , 5 , 6 , 7 ]. With the deletion of virulence-associated factors, attenuated strains that can induce protective immune responses against virulent parental virus challenge in pigs are promising live attenuated vaccines (LAVs) [ 8 ].…”