Nuclear soluble cGAS senses double-stranded DNA virus infection

Wu, Yunqin; Song, Kun; Hao, Wenzhuo; Li, Jack; Wang, Lingyan; Li, Shitao

doi:10.1038/s42003-022-03400-1

Cited by 17 publications

(12 citation statements)

References 46 publications

(36 reference statements)

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“…Herpes simplex virus 1 infection results in the release of cGAS from chromatin into the nuclear soluble fraction. Released nuclear soluble cGAS senses viral DNA and produces cGAMP, which subsequently induces the expression of type I IFN and IFN-stimulated genes ( 126 ). Moreover, nuclear cGAS interacts with protein arginine methyltransferase 5 (PRMT5) to catalyze the symmetric dimethylation of the histone H3 arginine 2 at Ifnb and Ifna4 promoters, thereby promoting the entry of IRF3 and inducing IFN production ( Figure 4F ) ( 127 ).…”

Section: Functions Of Nuclear Cgasmentioning

confidence: 99%

cGAS: action in the nucleus

Lu,

Zhao,

Chen

et al. 2024

Front. Immunol.

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As a canonical cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) plays a key role in innate immunity. In recent years, a growing number of studies have shown that cGAS can also be located in the nucleus and plays new functions such as regulating DNA damage repair, nuclear membrane repair, chromosome fusion, DNA replication, angiogenesis and other non-canonical functions. Meanwhile, the mechanisms underlying the nucleo-cytoplasmic transport and the regulation of cGAS activation have been revealed in recent years. Based on the current understanding of the structure, subcellular localization and canonical functions of cGAS, this review focuses on summarizing the mechanisms underlying nucleo-cytoplasmic transport, activity regulation and non-canonical functions of cGAS in the nucleus. We aim to provide insights into exploring the new functions of cGAS in the nucleus and advance its clinical translation.

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Section: Functions Of Nuclear Cgasmentioning

confidence: 99%

cGAS: action in the nucleus

Lu,

Zhao,

Chen

et al. 2024

Front. Immunol.

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“…DNA virus infection may result in the shedding and release of chromatin-bound cGAS into the nuclear soluble fraction. Nuclear soluble cGAS can sense viral DNA like cytoplasmic cGAS and mediate downstream IFN-I production, which, in turn, inhibits viral DNA replication ( Wu et al., 2022 ). Nuclear cGAS in dendric cells (DCs) can produce cGAMP after infection with HSV-1, although cGAMP levels are 200-fold lower than cytoplasmic cGAMP levels produced by herring testis DNA (HT-DNA) transfection ( Gentili et al., 2019 ).…”

Section: Physiological Functionsmentioning

confidence: 99%

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

Pan

Fei

et al. 2023

Zoological Research

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The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.

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“…It is possible that cGAS may also be activated within the nucleus upon DNA replication stress. A recent study has shown that nuclear soluble cGAS can be activated by Herpes Simplex Virus 1 (HSV‐1), a nuclear replicating DNA virus 68 . This leads to the possibility that cGAS can be activated in the nucleus by other forms of non‐chromatinized DNA, such as DNA fragments resulting from the processing of stalled replication forks and DNA breaks, or by unchromatinized DNA at the sites of fork stalling and DNA damage (Figure 3).…”

Section: Isg15 Is Induced Upon Dna Damage and Dna Replication Stressmentioning

confidence: 99%

ISG15: A link between innate immune signaling, DNA replication, and genome stability

Wardlaw

Petrini

2023

BioEssays

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Interferon stimulated gene 15 (ISG15) encodes a ubiquitin‐like protein that is highly induced upon activation of interferon signaling and cytoplasmic DNA sensing pathways. As part of the innate immune system ISG15 acts to inhibit viral replication and particle release via the covalent conjugation to both viral and host proteins. Unlike ubiquitin, unconjugated ISG15 also functions as an intracellular and extra‐cellular signaling molecule to modulate the immune response. Several recent studies have shown ISG15 to also function in a diverse array of cellular processes and pathways outside of the innate immune response. This review explores the role of ISG15 in maintaining genome stability, particularly during DNA replication, and how this relates to cancer biology. It puts forth the hypothesis that ISG15, along with DNA sensors, function within a DNA replication fork surveillance pathway to help maintain genome stability.

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Nuclear soluble cGAS senses double-stranded DNA virus infection

Cited by 17 publications

References 46 publications

cGAS: action in the nucleus

cGAS: action in the nucleus

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

ISG15: A link between innate immune signaling, DNA replication, and genome stability

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