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Autophagy induced by STING, an unnoticed and primordial function of cGAS

Cellular & Molecular Immunology volume 16, pages 683–684 (2019)Cite this article

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Cyclic GMP-AMP synthase (cGAS), combined with dsDNA, produces cyclic GMP-AMP (cGAMP) to stimulate STING and activates the kinases TBK1 and IKK to induce interferon and other cytokines, which play an important role in host defense. In addition to the traditional interferon inflammatory signaling pathway of cGAS, recently, Chen et al.1 discovered a new mechanism in which cGAS-cGAMP-STING activated autophagy through WIPI2 and ATG5. Autophagy is a process induced under various cellular stress conditions, such as oxygen deficit, nutrient deprivation, lack of growth factors, and infection, aiming to maintain the basic survival of cells or promote apoptosis of senescent cells.2,3 The activation of the autophagy-related (ATG)1/Unc-51-like kinase (ULK) complex is vital for autophagy induction. The ATG1/ULK1 complex phosphorylates or recruits its downstream proteins, contributing to autophagosome formation.3 Under the regulation of related genes, “cargo” is transferred to the lysosome and digested by various enzymes. In addition, cyclic GMP-AMP synthase (cGAS), which detects exogenous or self-damaged dsDNA in the cytoplasm after binding to dsDNA, produces cGAMP to activate the adaptor protein stimulator of interferon genes (STING), triggering the downstream pathway and secretion of interferon or other cytokines.4

Chen et al. discovered that STING, after treatment with cGAMP, not only induces the secretion of interferon or other cytokines but also initiates autophagy.1 The researchers found that STING from the sea anemone Nematostella vectensis (NvSTING) facilitates autophagy rather than inducing the production of interferon upon interacting with cGAMP.1 cGAMP from human or N. vectensis was shown to be highly conservative, and NvSTING does not contain the C-terminal domain, which is required for the activation of the interferon pathway.1 Moreover, truncated human STING(1–340) without the C-terminal domain still maintains NvSTING function after treatment with cGAMP. A mutation within amino acid residues 330–334 in the full-length STING resulted in a failure to induce autophagy and phosphorylation of TBK1 and IRF3 after treatment with cGAMP. In this report, the authors hypothesized that autophagy induced by STING is independent of TBK1-IRF3 activation and is a primordial function of the cGAS pathway.1

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No. 81773558), and Guangzhou Science and Technology Project (No. 201904010380).

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  1. These authors contributed equally: Junjie Yang, Xiaoshan Tang

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

    Junjie Yang, Xiaoshan Tang, Kutty Selva Nandakumar & Kui Cheng

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Correspondence to Kui Cheng.

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Yang, J., Tang, X., Nandakumar, K. et al. Autophagy induced by STING, an unnoticed and primordial function of cGAS. Cell Mol Immunol 16, 683–684 (2019). https://doi.org/10.1038/s41423-019-0240-2

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