Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (52), p.e2308853120
Main Authors: Qin, Fei, Cai, Baoshan, Cao, Runyu, Bai, Xuemei, Yuan, Jiahua, Zhang, Yuling, Liu, Yaxing, Chen, Tian, Liu, Feng, Sun, Wanwei, Zheng, Yi, Qi, Xiaopeng, Zhao, Wei, Liu, Bingyu, Gao, Chengjiang
Format: Article
Language:English
Subjects:
Amyotrophic Lateral Sclerosis
Animals
Biodegradation
Biological Sciences
Degradation
Endosomal Sorting Complexes Required for Transport - metabolism
Endosomes
Herpes simplex
Immune response
Immune system
Immunity, Innate - genetics
Inflammation
Innate immunity
Mice
Microorganisms
Mitochondrial DNA
Nucleotidyltransferases - metabolism
Proteolysis
Signal Transduction - physiology
Stimulators
Therapeutic targets
Ubiquitin-protein ligase
Ubiquitination
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Summary:The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2308853120