Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses

Wang, Chenguang; Guan, Yukun; Lv, Mengze; Zhang, Rui; Guo, Zhaoying; Wei, Xiaoming; Du, Xiaoxia; Yang, Jing; Li, Tong; Wan, Yi; Su, Xiao‐Dong; Huang, Xiao‐Jun; Jiang, Zhengfan

doi:10.1016/j.immuni.2018.03.017

Cited by 515 publications

(389 citation statements)

References 62 publications

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“…The possibility that Ca 2+ and Mn 2+ share transport pathways mediated by ECAs, BICATs, CAXs, and Ca 2+ channels, implies an interference of Mn 2+ in Ca 2+ signaling. In fact, Mn 2+ has been demonstrated to act as a signaling agent per se in humans (Wang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Manganese in Plants: From Acquisition to Subcellular Allocation

et al. 2020

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Manganese (Mn) is an important micronutrient for plant growth and development and sustains metabolic roles within different plant cell compartments. The metal is an essential cofactor for the oxygen-evolving complex (OEC) of the photosynthetic machinery, catalyzing the water-splitting reaction in photosystem II (PSII). Despite the importance of Mn for photosynthesis and other processes, the physiological relevance of Mn uptake and compartmentation in plants has been underrated. The subcellular Mn homeostasis to maintain compartmented Mn-dependent metabolic processes like glycosylation, ROS scavenging, and photosynthesis is mediated by a multitude of transport proteins from diverse gene families. However, Mn homeostasis may be disturbed under suboptimal or excessive Mn availability. Mn deficiency is a serious, widespread plant nutritional disorder in dry, well-aerated and calcareous soils, as well as in soils containing high amounts of organic matter, where bio-availability of Mn can decrease far below the level that is required for normal plant growth. By contrast, Mn toxicity occurs on poorly drained and acidic soils in which high amounts of Mn are rendered available. Consequently, plants have evolved mechanisms to tightly regulate Mn uptake, trafficking, and storage. This review provides a comprehensive overview, with a focus on recent advances, on the multiple functions of transporters involved in Mn homeostasis, as well as their regulatory mechanisms in the plant's response to different conditions of Mn availability.

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Section: Discussionmentioning

confidence: 99%

Manganese in Plants: From Acquisition to Subcellular Allocation

et al. 2020

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“…T he sensing of double-stranded DNA (dsDNA) by cyclic GMP-AMP synthase (cGAS) is a danger signal in cells (1,2), leading to conformational transitions within the cGAS sensor to form a catalytically competent pocket for generation of cyclic dinucleotide 2′,3′-cGAMP (3)(4)(5)(6)(7)(8), which then acts as second messenger by binding and activating stimulator of IFN genes (STING) and inducing the expression of type I IFN (3,(9)(10)(11). Notably, cGAS is essential for the immune response to many microbes that usually present long DNA at low abundance to the cytoplasm (12)(13)(14)(15)(16). Consistent with this distinction, cGAS exhibits a DNA length-dependent manner of activation, with longer DNA duplexes producing a significantly stronger immune response of cGAS (14,(17)(18)(19).…”

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confidence: 99%

Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation

Xie

Lama

Adura

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

152

107

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The cyclic GMP-AMP synthase (cGAS)-cGAMP-STING pathway plays a key role in innate immunity, with cGAS sensing both pathogenic and mislocalized DNA in the cytoplasm. Human cGAS (h-cGAS) constitutes an important drug target for control of antiinflammatory responses that can contribute to the onset of autoimmune diseases. Recent studies have established that the positively charged N-terminal segment of cGAS contributes to enhancement of cGAS enzymatic activity as a result of DNA-induced liquid-phase condensation. We have identified an additional cGAS CD -DNA interface (labeled site-C; CD, catalytic domain) in the crystal structure of a human SRY.cGAS CD -DNA complex, with mutations along this basic site-C cGAS interface disrupting liquid-phase condensation, as monitored by cGAMP formation, gel shift, spin-down, and turbidity assays, as well as time-lapse imaging of liquid droplet formation. We expand on an earlier ladder model of cGAS dimers bound to a pair of parallel-aligned DNAs to propose a multivalent interaction-mediated cluster model to account for DNA-mediated condensation involving both the N-terminal domain of cGAS and the site-C cGAS-DNA interface. We also report the crystal structure of the h-cGAS CD -DNA complex containing a triple mutant that disrupts the site-C interface, with this complex serving as a future platform for guiding cGAS inhibitor development at the DNA-bound h-cGAS level. Finally, we solved the structure of RU.521 bound in two alternate alignments to apo h-cGAS CD , thereby occupying more of the catalytic pocket and providing insights into further optimization of active-site-binding inhibitors.h-cGAS-DNA complex | DNA-binding cGAS mutations | multivalent interactions | liquid-phase condensation

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“…mtDNA depletion (Extended Data Fig. 2j) by ethidium bromide 28 did not affect Mn 2+ -induced inflammasome activation either (Extended Data Fig. 2k, l).…”

Section: Resultsmentioning

confidence: 89%

“…Mn 2+ was released from mitochondria and Golgi apparatus upon virus infection and accumulated in the cytosol where it bound directly to cGAS, enhancing the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity. Mn 2+ also enhanced cGAMP-STING binding affinity 28 . Importantly, Mn 2+ was a potent innate immune stimulator, inducing type I-IFN and cytokine production in the absence of any infection.…”

Section: Main Textmentioning

confidence: 87%

The Manganese Salt (MnJ) Functions as A Potent Universal Adjuvant

Zhang

Wang

Guan

et al. 2019

Preprint

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15Aluminum adjuvants have been used for a century in various vaccines due to its ability to 16 potentiate humoral immunity and safety records since 1920s. Manganese is an essential 17 micronutrient required for diverse biological activities in cells. We previously found that Mn 2+ is a 18 strong type I-interferon stimulator activating the cGAS-STING pathway. Herein we report that a 19 colloidal manganese salt (MnJ) is a potent adjuvant to induce both humoral and cellular immune 20 responses, particularly CTL activation. When administrated intranasally, MnJ was also a strong 21 mucosal adjuvant, inducing high levels of IgA antibodies. MnJ strongly promoted dendritic cell 22 maturation and antigen-specific T cell activation. Interestingly, IL-1/-18 induction and release by 23Mn 2+ -activated ASC-mediated inflammasomes were not observed. MnJ showed great adjuvant 24 effects to all tested antigens including inactivated viruses, recombinant proteins and peptides by 25 either intramuscular or intranasal immunization. These findings may have implications in 26 developing potent but safe Mn 2+ -containing vaccines. 27

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Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses

Cited by 515 publications

References 62 publications

Manganese in Plants: From Acquisition to Subcellular Allocation

Manganese in Plants: From Acquisition to Subcellular Allocation

Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation

The Manganese Salt (MnJ) Functions as A Potent Universal Adjuvant

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