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Autophagy induction via STING trafficking is a primordial function of the cGAS pathway

Author

Listed:
  • Xiang Gui

    (University of Texas Southwestern Medical Center)

  • Hui Yang

    (University of Texas Southwestern Medical Center)

  • Tuo Li

    (University of Texas Southwestern Medical Center)

  • Xiaojun Tan

    (University of Texas Southwestern Medical Center)

  • Peiqing Shi

    (University of Texas Southwestern Medical Center)

  • Minghao Li

    (University of Texas Southwestern Medical Center)

  • Fenghe Du

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Zhijian J. Chen

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self DNA in the cytoplasm1. Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines2–6. Here we report that STING also activates autophagy through a mechanism that is independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) and the Golgi in a process that is dependent on the COP-II complex and ARF GTPases. STING-containing ERGIC serves as a membrane source for LC3 lipidation, which is a key step in autophagosome biogenesis. cGAMP induced LC3 lipidation through a pathway that is dependent on WIPI2 and ATG5 but independent of the ULK and VPS34–beclin kinase complexes. Furthermore, we show that cGAMP-induced autophagy is important for the clearance of DNA and viruses in the cytosol. Interestingly, STING from the sea anemone Nematostella vectensis induces autophagy but not interferons in response to stimulation by cGAMP, which suggests that induction of autophagy is a primordial function of the cGAS–STING pathway.

Suggested Citation

  • Xiang Gui & Hui Yang & Tuo Li & Xiaojun Tan & Peiqing Shi & Minghao Li & Fenghe Du & Zhijian J. Chen, 2019. "Autophagy induction via STING trafficking is a primordial function of the cGAS pathway," Nature, Nature, vol. 567(7747), pages 262-266, March.
  • Handle: RePEc:nat:nature:v:567:y:2019:i:7747:d:10.1038_s41586-019-1006-9
    DOI: 10.1038/s41586-019-1006-9
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    Cited by:

    1. Xintao Tu & Ting-Ting Chu & Devon Jeltema & Kennady Abbott & Kun Yang & Cong Xing & Jie Han & Nicole Dobbs & Nan Yan, 2022. "Interruption of post-Golgi STING trafficking activates tonic interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Lei Gao & Fushun Liu & Ruilian Liu, 2023. "The Mechanism of Aerobic Exercise Regulating the PI3K/Akt-mTOR Signaling Pathway Intervenes in Hippocampal Neuronal Apoptosis in Vascular Dementia Rats," IJERPH, MDPI, vol. 20(3), pages 1-10, January.
    3. Matteo Gentili & Bingxu Liu & Malvina Papanastasiou & Deborah Dele-Oni & Marc A. Schwartz & Rebecca J. Carlson & Aziz M. Al’Khafaji & Karsten Krug & Adam Brown & John G. Doench & Steven A. Carr & Nir , 2023. "ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Annemarie Steiner & Katja Hrovat-Schaale & Ignazia Prigione & Chien-Hsiung Yu & Pawat Laohamonthonkul & Cassandra R. Harapas & Ronnie Ren Jie Low & Dominic Nardo & Laura F. Dagley & Michael J. Mlodzia, 2022. "Deficiency in coatomer complex I causes aberrant activation of STING signalling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.

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