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S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens

Author

Listed:
  • Mutian Jia

    (Shandong University
    Shandong University)

  • Li Chai

    (Shandong University
    Shandong University)

  • Jie Wang

    (Shandong University
    Shandong University)

  • Mengge Wang

    (Shandong University
    Shandong University)

  • Danhui Qin

    (Shandong University
    Shandong University)

  • Hui Song

    (Shandong University
    Shandong University)

  • Yue Fu

    (Shandong University
    Shandong University)

  • Chunyuan Zhao

    (Shandong University)

  • Chengjiang Gao

    (Shandong University
    Shandong University)

  • Jihui Jia

    (Shandong University)

  • Wei Zhao

    (Shandong University
    Shandong University)

Abstract

Oxidative (or respiratory) burst confers host defense against pathogens by generating reactive species, including reactive nitrogen species (RNS). The microbial infection-induced excessive RNS damages many biological molecules via S-nitrosothiol (SNO) accumulation. However, the mechanism by which the host enables innate immunity activation during oxidative burst remains largely unknown. Here, we demonstrate that S-nitrosoglutathione (GSNO), the main endogenous SNO, attenuates innate immune responses against herpes simplex virus-1 (HSV-1) and Listeria monocytogenes infections. Mechanistically, GSNO induces the S-nitrosylation of stimulator of interferon genes (STING) at Cys257, inhibiting its binding to the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Alcohol dehydrogenase 5 (ADH5), the key enzyme that metabolizes GSNO to decrease cellular SNOs, facilitates STING activation by inhibiting S-nitrosylation. Concordantly, Adh5 deficiency show defective STING-dependent immune responses upon microbial challenge and facilitates viral replication. Thus, cellular oxidative burst-induced RNS attenuates the STING-mediated innate immune responses to microbial infection, while ADH5 licenses STING activation by maintaining cellular SNO homeostasis.

Suggested Citation

  • Mutian Jia & Li Chai & Jie Wang & Mengge Wang & Danhui Qin & Hui Song & Yue Fu & Chunyuan Zhao & Chengjiang Gao & Jihui Jia & Wei Zhao, 2024. "S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46212-z
    DOI: 10.1038/s41467-024-46212-z
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