Macroautophagy/autophagy has been exploited by many viruses, including foot-and-mouth disease virus (FMDV), to promote viral replication, but the underlying mechanisms of the interaction between autophagy and the innate immune response remain unclear. Here, researchers show that histone deacetylase 8 (HDAC8) inhibits FMDV replication by regulating innate immune signaling and antiviral responses. To counteract the effect of HDAC8, FMDV utilizes autophagy to promote HDAC8 degradation. Further data revealed that the FMDV structural protein VP3 promotes autophagy during viral infection and interacts with and degrades HDAC8 through an AKT-MTOR-ATG5-dependent autophagy pathway. These studies demonstrate that FMDV has evolved a strategy to counteract the host's antiviral activity by degrading proteins that regulate the innate immune response during viral infection through autophagy.
Innate immunity is the first line of defense against viral infections. To investigate the function of HDAC8 in regulating immune responses, researchers examined the expression of interferon-related genes using control and HDAC8 gene knockout cell lines. As shown in Figure 1A, they detected the expression of FMDV structural proteins using FMDV polyclonal antibodies. Compared to control cells, knocking out HDAC8 in the PK-15 cell line significantly reduced the phosphorylation levels of TBK1 and IRF3 during FMDV infection, which are key regulators of interferon production and subsequent immune responses, leading to increased viral replication in the knockout cells. Furthermore, the phosphorylation levels of TBK1 and IRF3 were significantly enhanced during FMDV infection in HDAC8-overexpressing PK-15 cells, thereby attenuating viral replication (Figure 1B). Real-time quantitative PCR results also showed that the expression levels of IFNB, IFIT2/ISG54, CCL5, OAS, and TNF were significantly reduced in HDAC8 knockout cells compared to control cells, while they were significantly increased in HDAC8-overexpressing cells (Figure 1C, D). These data consistently indicate that HDAC8 regulates the innate immune response during FMDV infection.
Figure 1. HDAC8 involves in the antiviral signaling pathway. (Zhang H, et al., 2023)