TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Stimulator of interferon response cGAMP interactor 1 (STING1) is crucial for innate immunity.
• STING1 primarily induces type I interferon (IFN) responses.
• STING1's non-canonical functions in macrophages remain underexplored.

Purpose of the Study:

• To investigate IFN-independent roles of STING1 in macrophages.
• To identify regulatory mechanisms of STING1 signaling.
• To elucidate the function of transcription factors TFEB and TFE3 in STING1-mediated immunity.

Main Methods:

• Transcriptomic analysis of macrophages.
• Investigating STING1 activation of transcription factors TFEB and TFE3.
• Assessing the impact of TFEB/TFE3 depletion or overexpression on STING1 signaling.
• Measuring autophagy, lysosomal biogenesis, and IFN production.

Main Results:

• STING1 upregulates lysosomal and autophagic genes via TFEB and TFE3 activation.
• TFEB and TFE3 enhance autophagy, lysosomal biogenesis, and acidification.
• TFEB and TFE3 modulate IRF3 activation, influencing IFN production and cell death.
• Depletion of TFEB/TFE3 increases IFN production and cell death, while overexpression reduces them.

Conclusions:

• TFEB and TFE3 are key regulators of STING1's IFN-independent functions.
• STING1 signaling involves TFEB/TFE3 in controlling autophagy and lysosomal pathways.
• These transcription factors play a critical role in STING1-mediated innate antiviral immunity.