Key Roles of MiT Transcription Factors in Innate Immunity and Inflammation

Microphthalmia/TFE (MiT) transcription factors (TFs), such as transcription factor EB (TFEB) and transcription factor E3 (TFE3), are emerging as key regulators of innate immunity and inflammation. Rapid progress in the field requires a focused update on the latest advances. Recent studies show that TFEB and TFE3 function in innate immune cells to regulate antibacterial and antiviral responses downstream of phagocytosis, interferon (IFN)-γ, lipopolysaccharide (LPS), and adenosine receptors. Moreover, overexpression of TFEB or TFE3 can drive inflammation in vivo, such as in atherosclerosis, while in other scenarios they can perform anti-inflammatory functions. MiT factors may constitute potential therapeutic targets for a broad range of diseases; however, to harness their therapeutic potential, sophisticated ways to manipulate MiT factor activity safely and effectively must be developed. TFEB, TFE3, and related MiT TFs are broadly expressed in mammals.Under resting or homeostatic conditions, TFEB and TFE3 reside in the cytosol; their activation entails nuclear translocation, which is triggered by many distinct stimuli.Recently identified upstream regulation of TFEB and/or TFE3 in innate immune cells includes phagocytosis, lysosome damage, IFN-γ, LPS, and extracellular ATP.Recently identified downstream functions of TFEB and/or TFE3 in innate immune cells include autophagy and lysosomal biogenesis, bacterial killing, proinflammatory cytokine production, macrophage classical activation, antiviral responses, and dendritic cell migration.Multiple feedback loops control TFEB and TFE3, mandating sophisticated approaches to safely control their activities for therapeutic purposes.