PIKfyve, a class III lipid kinase, is required for TLR-induced type I IFN production via modulation of ATF3 (THER4P.890)

Abstract Type I IFN plays a key role in anti-viral responses. It also has been shown that deregulation of Type I IFN expression following abnormal activation of TLRs contributes to pathogenesis of systemic lupus erythematosus. In this study we find PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3P and synthesizes phosphatidylinositol (3,5)P2, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by binding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLR-mediated induction of type I IFN, which may provide new therapeutic indication for PIKfyve inhibitor.