IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes

Alpha-kinase 1 (ALPK1) is an immune receptor sensing the bacterial nucleotide sugar ADP-heptose. ALPK1 phosphorylates TIFA leading to its oligomerization and downstream NF-κB activation. Specific mutations in ALPK1 are associated with an autoinflammatory syndrome termed ROSAH and with spiradenoma (skin cancers with sweat gland differentiation). This study investigated ALPK1 responses in human mononuclear cells and demonstrates that human mononuclear cells have distinct abilities to respond to ADP-heptose. Notably, IFN-γ is required to license the ALPK1/TIFA pathway in monocytes, while it was dispensable for the responsiveness of B cells. IFN-γ induced TIFA upregulation in monocytes, and TIFA induction was sufficient to recapitulate the licensing effect of IFN-γ. IFN-γ treatment promoted the phenotypic expression of pathogenic ALPK1 mutations. The licensing effect of IFN-γ in monocytes was blocked by JAK inhibitors. These findings underscore the critical role of IFN-γ in ALPK1 function and suggest JAK inhibitors as potential therapies for ALPK1-related inflammatory conditions.