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

Nature communications | 2024

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.

Pubmed ID: 38409248 RIS Download

Associated grants

  • Agency: National Natural Science Foundation of China (National Science Foundation of China),
    Id: 31870866
  • Agency: National Natural Science Foundation of China (National Science Foundation of China),
    Id: 82125020
  • Agency: National Natural Science Foundation of China (National Science Foundation of China),
    Id: 82101855
  • Agency: National Natural Science Foundation of China (National Science Foundation of China),
    Id: 82321002
  • Agency: China Postdoctoral Science Foundation,
    Id: 2021T140406

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