Role of MiT family transcription factors in type I interferon and anti-bacterial defense 2352

Abstract Description MiT family transcription factors, TFE3 and TFEB (TFEs), play crucial roles in starvation responses and lysosomal biogenesis. Notably, the expanding functions of TFEs emerging from recent studies suggest a broader role for them in innate immune responses. Consistent with this, our latest study identified a key role for TFE3 in the TLR4-dependent type I interferon (IFN) response to a clinically significant human pathogen, enterohemorrhagic Escherichia coli (EHEC). However, whether TFE3 functions beyond TLR4 signaling as a universal mechanism promoting type I IFN expression driven by all pattern recognition receptors (PRRs) and whether TFEB has a similar role remained unknown. Remarkably, our current study reveals that both TFE3 and TFEB are essential for type I IFN expression elicited by endosomal PRRs such as TLR4 and TLR3, and cytosolic PRRs such as cGAS in macrophages. PRR stimulation results in rapid activation of TFEs and TFEs appear to regulate IFN synthesis by promoting IRF3 phosphorylation. Importantly, our data also show that TFE-mediated-IFNβ production is vital for human intestinal epithelial cell (IEC) resistance to EHEC; deficiency of TFE3 and TFEB resulted in higher EHEC colonization of IECs and pretreating the cells with recombinant IFNβ led to a reversal of this increased EHEC colonization of TFE-deficient cells. Together, these findings identify a novel MiT transcription factor-based mechanism that broadly regulates type I IFN and anti-bacterial responses. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)