Dynamic regulation of TBK1 lactylation shapes antiviral immune responses

The precise control of type I interferon (IFN-I) signaling is critical for effective antiviral defense and the maintenance of immune balance. In this study, we revealed a dynamic regulatory network involving lactylation–delactylation of TANK binding kinase 1 (TBK1), a pivotal kinase of IFN-I signaling, that finely tunes antiviral immune responses. Viral infection triggers the lactylation of TBK1 at K241, which is mediated by alanyl-tRNA synthetase 1 (AARS1), which potentiates IFN-I signaling to establish an antiviral state. Notably, we identified sirtuin 6 (SIRT6) as a pivotal “eraser” responsible for reversing this process by removing TBK1 lactylation. This action initiates a stringent negative feedback loop, leading to delactylated TBK1 being targeted by the E3 ligase SIAH2 for K48-linked polyubiquitination and subsequent selective autophagic degradation via p62. In vivo experiments revealed that myeloid-specific deletion of Sirt6 in mice resulted in sustained TBK1 lactylation and increased IFN-I production during VSV infection, ultimately improving survival. This intricate regulatory circuit not only maintains an appropriate IFN-I response to prevent excessive immune activation but also highlights the potential of targeting lactylation as a novel therapeutic strategy for chronic infections and autoimmune diseases associated with TBK1 dysregulation.