TY - JOUR
T1 - TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling
AU - Tapia, Pablo J.
AU - Martina, José A.
AU - Contreras, Pablo S.
AU - Prashar, Akriti
AU - Jeong, Eutteum
AU - De Nardo, Dominic
AU - Puertollano, Rosa
N1 - Publisher Copyright:
© This work was authored as part of the Contributor’s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.
PY - 2025
Y1 - 2025
N2 - 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 overexpression led to reduced IRF3 activation and an almost complete inhibition of IFN synthesis and secretion, resulting in decreased CASP3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity. Abbreviation: ACOD1/IRG1, aconitate decarboxylase 1; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; CGAS, cyclic GMP-AMP synthase; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; GABARAP, GABA type A receptor-associated protein; HSV-1, herpes simplex virus type; iBMDMs, immortalized bone marrow-derived macrophages; IFN, type I interferon; IFNB, interferon beta; IKBKE, inhibitor of nuclear factor kappa B kinase subunit epsilon; IRF3, interferon regulatory factor 3; LAMP1, lysosomal associated membrane protein 1; LAMP2, lysosomal associated membrane protein 2; MTORC1, mechanistic target of rapamycin kinase complex 1; RPS6, ribosomal protein S6; STING1, stimulator of interferon response cGAMP interactor 1; TBK1, TANK binding kinase 1; TFE3, transcription factor binding to IGHM enhancer 3; TFEB, transcription factor EB.
AB - 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 overexpression led to reduced IRF3 activation and an almost complete inhibition of IFN synthesis and secretion, resulting in decreased CASP3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity. Abbreviation: ACOD1/IRG1, aconitate decarboxylase 1; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; CGAS, cyclic GMP-AMP synthase; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; GABARAP, GABA type A receptor-associated protein; HSV-1, herpes simplex virus type; iBMDMs, immortalized bone marrow-derived macrophages; IFN, type I interferon; IFNB, interferon beta; IKBKE, inhibitor of nuclear factor kappa B kinase subunit epsilon; IRF3, interferon regulatory factor 3; LAMP1, lysosomal associated membrane protein 1; LAMP2, lysosomal associated membrane protein 2; MTORC1, mechanistic target of rapamycin kinase complex 1; RPS6, ribosomal protein S6; STING1, stimulator of interferon response cGAMP interactor 1; TBK1, TANK binding kinase 1; TFE3, transcription factor binding to IGHM enhancer 3; TFEB, transcription factor EB.
KW - Autophagy
KW - immune response
KW - lysosomes
KW - STING1
KW - TFE3
KW - TFEB
UR - https://www.scopus.com/pages/publications/105003134873
U2 - 10.1080/15548627.2025.2487036
DO - 10.1080/15548627.2025.2487036
M3 - Article
C2 - 40195022
AN - SCOPUS:105003134873
SN - 1554-8627
VL - 21
SP - 2028
EP - 2045
JO - Autophagy
JF - Autophagy
IS - 9
ER -