Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation

Jia, Mutian; Wang, Yuanyuan; Wang, Jie; Qin, Danhui; Wang, Mengge; Chai, Li; Fu, Yue; Zhao, Chenyang; Gao, Chengjiang; Jia, Jihui; Zhao, Wei

doi:10.1038/s41467-023-36332-3

Cited by 24 publications

(10 citation statements)

References 52 publications

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“…Recently, it was shown that ARF1 may also have a role in autophagy. However, our data show that cGAS-STING activation by the ARF1 R99C mutation is not mediated by autophagy 55 . Future studies are needed to genetically dissect the relative contribution of autophagy-mediated STING turnover and ARF1-mediated STING recycling to overall cGAS/STING signal termination.…”

Section: Discussioncontrasting

confidence: 63%

ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

Hirschenberger,

Lepelley,

Rupp

et al. 2023

Nat Commun

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Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling.

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Section: Discussioncontrasting

confidence: 63%

ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

Hirschenberger,

Lepelley,

Rupp

et al. 2023

Nat Commun

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“…Myristic acid has previously been described to have antifungal [89,90] and antiinflammatory effects [91]. Additionally, myristic acid has been identified as a metabolic checkpoint that regulates autophagy and type I IFN responses [92]. In the present study, we confirmed that the IL-10 production of LPS-treated moDCs can be inhibited in the presence of myristic acid.…”

Section: Discussionsupporting

confidence: 82%

Radiation-Detoxified Form of Endotoxin Effectively Activates Th1 Responses and Attenuates Ragweed-Induced Th2-Type Airway Inflammation in Mice

Bácsi,

Ágics,

Pázmándi

et al. 2024

IJMS

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Urbanization with reduced microbial exposure is associated with an increased burden of asthma and atopic symptoms. Conversely, environmental exposure to endotoxins in childhood can protect against the development of allergies. Our study aimed to investigate whether the renaturation of the indoor environment with aerosolized radiation-detoxified lipopolysaccharide (RD-LPS) has a preventative effect against the development of ragweed-induced Th2-type airway inflammation. To explore this, cages of six-week-old BALB/c mice were treated daily with aerosolized native LPS (N-LPS) or RD-LPS. After a 10-week treatment period, mice were sensitized and challenged with ragweed pollen extract, and inflammatory cell infiltration into the airways was observed. As dendritic cells (DCs) play a crucial role in the polarization of T-cell responses, in our in vitro experiments, the effects of N-LPS and RD-LPS were compared on human monocyte-derived DCs (moDCs). Mice in RD-LPS-rich milieu developed significantly less allergic airway inflammation than mice in N-LPS-rich or common environments. The results of our in vitro experiments demonstrate that RD-LPS-exposed moDCs have a higher Th1-polarizing capacity than moDCs exposed to N-LPS. Consequently, we suppose that the aerosolized, non-toxic RD-LPS applied in early life for the renaturation of urban indoors may be suitable for the prevention of Th2-mediated allergies in childhood.

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“…Myristic acid has recently emerged as a regulator of STING degradation via N-myristoylation of ARF1, which is involved in directing the membrane trafficking and autophagic degradation of STING, thereby limiting cGAS-STING-induced interferon response. Upon viral infection the production of myristic acid is reduced due to a disruption in the cellular lipid metabolism, which alleviates autophagy-dependent STING degradation ( 160 ).…”

Section: Interactions Of Autophagy With the Cgas-sting Pathwaymentioning

confidence: 99%

The interplay between autophagy and cGAS-STING signaling and its implications for cancer

Schmid,

Fischer,

Engl

et al. 2024

Front. Immunol.

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Autophagy is an intracellular process that targets various cargos for degradation, including members of the cGAS-STING signaling cascade. cGAS-STING senses cytosolic double-stranded DNA and triggers an innate immune response through type I interferons. Emerging evidence suggests that autophagy plays a crucial role in regulating and fine-tuning cGAS-STING signaling. Reciprocally, cGAS-STING pathway members can actively induce canonical as well as various non-canonical forms of autophagy, establishing a regulatory network of feedback mechanisms that alter both the cGAS-STING and the autophagic pathway. The crosstalk between autophagy and the cGAS-STING pathway impacts a wide variety of cellular processes such as protection against pathogenic infections as well as signaling in neurodegenerative disease, autoinflammatory disease and cancer. Here we provide a comprehensive overview of the mechanisms involved in autophagy and cGAS-STING signaling, with a specific focus on the interactions between the two pathways and their importance for cancer.

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Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation

Cited by 24 publications

References 52 publications

ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

Radiation-Detoxified Form of Endotoxin Effectively Activates Th1 Responses and Attenuates Ragweed-Induced Th2-Type Airway Inflammation in Mice

The interplay between autophagy and cGAS-STING signaling and its implications for cancer

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