2. Academic Validation
  3. Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis

Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis

  • Immunity. 2023 Nov 15:S1074-7613(23)00458-2. doi: 10.1016/j.immuni.2023.11.001.
Ruoxi Zhang 1,  Chunhua Yu 1,  Herbert J Zeh 1,  Haichao Wang 2,  Guido Kroemer 3,  Daniel J Klionsky 4,  Timothy R Billiar 5,  Rui Kang 6,  Daolin Tang 7
Affiliations

Affiliations

  • 1 Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Laboratory of Emergency Medicine, North Shore University Hospital and the Feinsteins Institute for Medical Research, Manhasset, NY 11030, USA.
  • 3 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.
  • 4 Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5 Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
  • 6 Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: rui.kang@utsouthwestern.edu.
  • 7 Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: daolin.tang@utsouthwestern.edu.
PMID: 38016467 DOI: 10.1016/j.immuni.2023.11.001
Abstract

Extensive studies demonstrate the importance of the STING1 (also known as STING) protein as a signaling hub that coordinates immune and autophagic responses to ectopic DNA in the cytoplasm. Here, we report a nuclear function of STING1 in driving the activation of the transcription factor Aryl Hydrocarbon Receptor (AHR) to control gut microbiota composition and homeostasis. This function was independent of DNA sensing and Autophagy and showed competitive inhibition with cytoplasmic cyclic guanosine monophosphate (GMP)-AMP synthase (CGAS)-STING1 signaling. Structurally, the cyclic dinucleotide binding domain of STING1 interacted with the AHR N-terminal domain. Proteomic analyses revealed that STING1-mediated transcriptional activation of AHR required additional nuclear partners, including positive and negative regulatory proteins. Although AHR ligands could rescue colitis pathology and dysbiosis in wild-type mice, this protection was abrogated by mutational inactivation of STING1. These findings establish a key framework for understanding the nuclear molecular crosstalk between the microbiota and the immune system.

Keywords

AHR; STING1; gut microbiota; inflammatory bowel disease; innate immunity.

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