TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models

Loss-of-function mutations in TANK-binding kinase 1 (TBK1) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology, but the mechanisms beyond impaired autophagy remain undefined. Here, we identify a TBK1-IFNβ-immunoproteasome axis as a novel autophagy-independent proteostatic pathway regulating TDP-43 clearance. TBK1 is activated by aggregation-prone monomeric TDP-43 via physical association, and this activation alleviates TDP-43 pathology in neuronal cells. TBK1 subsequently induces IFNβ expression, which upregulates the immunoproteasome to promote degradation of monomeric TDP-43 in neurons, including human iPSC-derived lower motor neurons. Importantly, IFNβ receptor expression is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. Furthermore, heterozygous Tbk1 deletion in SOD1^G93A mice impairs immunoproteasome induction and increases polyubiquitinated protein accumulation in spinal cords, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that impairment of the TBK1-IFNβ-immunoproteasome axis represents an autophagy-independent mechanism contributing to the development of TDP-43 pathology in ALS and FTD.