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

Mutian Jia, Li Chai, Jie Wang, Mengge Wang, Danhui Qin, Hui Song, Yue Fu, Chunyuan Zhao, Chengjiang Gao, Jihui Jia and Wei Zhao ()
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Mutian Jia: Shandong University
Li Chai: Shandong University
Jie Wang: Shandong University
Mengge Wang: Shandong University
Danhui Qin: Shandong University
Hui Song: Shandong University
Yue Fu: Shandong University
Chunyuan Zhao: Shandong University
Chengjiang Gao: Shandong University
Jihui Jia: Shandong University
Wei Zhao: Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46212-z

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