Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity

Precise regulation of type I interferon (IFN-I) signaling is crucial for effective immune defense against infectious diseases. However, the molecular mechanisms governing this pathway are not fully understood. Here, we uncover a novel role for palmitoylation in enhancing anti-malarial immune response. Our findings reveal that ZDHHC9 enhances the IFN-I signaling by palmitoylating TBK1 at cysteine 292. Following infection with Plasmodium yoelii N67, the delicate balance between palmitoylation and depalmitoylation of TBK1 is disrupted. Specifically, upregulation of APT2 promotes persistent depalmitoylation of TBK1 and triggers its selective autophagic degradation via K48-linked polyubiquitination at lysine 251/372 by E3 ligase TRIM27. This process acts as a recognition signal for the cargo receptor NDP52, resulting in inhibition of the IFN-I pathway. Notably, inhibition of APT2 using ML349 elevates IFN-I levels and improves survival rates against N67 infection. Our findings establish that targeting APT2-mediated TBK1 depalmitoylation represents a promising therapeutic strategy, not only for combating against malaria but also for potential addressing diseases associated with dysregulated IFN-I signaling.