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TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling [AM_NIH_RNASeq_50538]

ABSTRACT: STING1 is an essential component of the innate immune defense against a wide variety of pathogens. Whereas induction of Type I interferon (IFN) responses is one of the best-defined functions of STING1, our transcriptomic analysis revealed IFN-independent activities of STING1 in macrophages, including transcriptional upregulation of numerous lysosomal and autophagic genes. This upregulation was mediated by the STING1-induced activation of the transcription factors TFEB and TFE3, and led to increased autophagy, lysosomal biogenesis, and lysosomal acidification. TFEB and TFE3 also modulated IFN-dependent STING1 signaling by controlling IRF3 activation. IFN production and cell death were increased in TFEB and TFE3 depleted iBMDMs. Conversely, TFEB over-expression led to reduced IRF3 activation and an almost complete inhibition of interferon synthesis and secretion, resulting in decrease caspase-3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE281234 | GEO | 2025/04/08

REPOSITORIES: GEO

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

Project description:STING1 is an essential component of the innate immune defense against a wide variety of pathogens. Whereas induction of Type I interferon (IFN) responses is one of the best-defined functions of STING1, our transcriptomic analysis revealed IFN-independent activities of STING1 in macrophages, including transcriptional upregulation of numerous lysosomal and autophagic genes. This upregulation was mediated by the STING1-induced activation of the transcription factors TFEB and TFE3, and led to increased autophagy, lysosomal biogenesis, and lysosomal acidification. TFEB and TFE3 also modulated IFN-dependent STING1 signaling by controlling IRF3 activation. IFN production and cell death were increased in TFEB and TFE3 depleted iBMDMs. Conversely, TFEB over-expression led to reduced IRF3 activation and an almost complete inhibition of interferon synthesis and secretion, resulting in decrease caspase-3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity.

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