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A chosen STING with a PERKy trail

Nature Cell Biology volume 24, pages 602–604 (2022)Cite this article

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Cytosolic DNA sensing by the cGAS–STING pathway is critical for sustaining an innate immune defense program. A new study shows that the cGAS–STING pathway signals by a non-canonical mechanism to control protein translation through the unfolded protein response sensor PERK, and thereby contributes to cellular senescence and organ fibrosis.

Innate immunity not only serves as a host defense response against pathogen infection, but also its hyperactivation contributes to autoimmunity. DNA derived from pathogens or damaged cells bind to the well-characterized cytosolic DNA sensor cGAS (cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) (cGAMP) synthase), which engages innate immune responses predominantly through the induction of interferons. Autoinhibited cGAS in the absence of the double-stranded DNA has two DNA-binding domains and a nucleotidyltransferase domain2,3. DNA binding results in a conformational change that produces cGAMP, a secondary messenger that activates STING (stimulator of interferon genes), an ER membrane–associated protein adaptor. Activated STING translocates from the ER to the Golgi, where C-terminal STING recruits and activates the kinase TBK1, which in turn phosphorylates the transcription factor IRF3; this results in dimerization of IRF3 and its subsequent translocation into the nucleus. STING also activates the transcription factor NF-κB pathway, which together with IRF3 induces the expression of interferons and inflammatory cytokines and numerous interferon-stimulated genes4.

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Fig. 1: Signalling mechanism and function of non-canonical PERK activation by cGAS–STING at the ER to regulate mRNA translation.
Fig. 2: Pathological roles of the cGAS–STING pathway in organ-specific diseases.

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Acknowledgements

Funded by FONDECYT 1140549, ANID-FONDAP-15150012, ICM- P09-015-F (C.H.), and FONDECYT 3180427 (Y.H.).

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Authors and Affiliations

  1. Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile

    Younis Hazari & Claudio Hetz

  2. FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago, Chile

    Claudio Hetz

  3. Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile

    Claudio Hetz

  4. Buck Institute for Research on Aging, Novato, CA, USA

    Claudio Hetz

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  1. Younis Hazari
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Correspondence to Claudio Hetz.

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Hazari, Y., Hetz, C. A chosen STING with a PERKy trail. Nat Cell Biol 24, 602–604 (2022). https://doi.org/10.1038/s41556-022-00905-z

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