TDP43 negatively regulates TBK1-mediated IFN1 production through IRF7 pathway in neurodegenerative diseases

Mutations in the genes encoding TAR DNA-binding protein 43 (TDP43) or TANK-binding kinase 1 (TBK1) have been strongly associated with neurological disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP43 is a key component of pathological protein aggregates found in more than 90% of ALS cases, while TBK1 plays a critical role in innate immune signaling and autophagy. Despite these associations, the precise molecular mechanisms linking TDP43 or TBK1 dysfunction to neurodegeneration remain poorly understood. The present study examined the impact of TDP43 on TBK1-mediated type I interferon (IFN1) production in HEK-293T cells. The findings demonstrated that co-expression of TDP43 and TBK1 resulted in a dose-dependent reduction in TBK1 and interferon regulatory factor (IRF) 7 protein levels. In addition, it led to decreased phosphorylation of IRF3 and TBK1. Interestingly, TDP43 knockout cells displayed elevated IRF7 protein levels. Moreover, co-expression of TDP43 and TBK1 significantly suppressed the IFN1 inductions and associated pro-inflammatory cytokines, a suppression reversed by IRF7 overexpression. Further, mechanistic analysis demonstrated that TDP43 facilitates TBK1 degradation through autophagy, resulting in diminished IFN1 induction. These findings uncover a new pathway through which TDP43 disrupts TBK1-mediated signaling through IRF7, potentially contributing to neurodegeneration. Overall, the disrupted TBK1-IRF7-IFN1 axis may therefore represent a critical pathway in TDP43-associated neurodegenerative diseases, offering potential targets for therapeutic intervention.