Tao Wang,Rui Luo,Jing Zhang,Jing Lan,Zhanhao Lu,Huanjie Zhai,Lian-Feng Li,Yuan Sun,Hua-Ji Qiu

Emerg Microbes Infect.2024 Mar 19:2333381.doi: 10.1080/22221751.2024.2333381. Online ahead of print.

Abstract

African swine fever (ASF) is a highly contagious, often fatal viral disease caused by African swine fever virus (ASFV) that imposes a substantial economic burden on the global pig industry each year. When screening for the regulation of virus replication 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, despite encoding 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 IL-1 β  and TNF- α  during the early stages of infection in 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; IKKβ; IκBα; MGF300-4L; chaperone-mediated autophagy.