Allosteric coupling between Mn2+ and dsDNA controls the catalytic efficiency and fidelity of cGAS

Hooy, Richard M.; Massaccesi, Guido; Rousseau, Kimberly E; Chattergoon, Michael A.; Sohn, Jungsan

doi:10.1093/nar/gkaa084

Cited by 67 publications

(65 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, Mn 2+ readily activates cells because Mn 2+ is actively and efficiently transported into cells, with an intracellular Mn 2+ concentration approximately ten times higher than the extracellular one, by various transporters including the divalent metal transporter (DMT1), Zn 2+ , and Ca 2+ transporters. 23 , 26 Moreover, more recent studies demonstrated that Mn 2+ directly activates cGAS independent of DNA and triggers a distinct catalytic synthesis of 2′3′-cGAMP, 63 , 64 strengthening the potential applications of Mn 2+ as a novel STING agonist to boost antitumor and antiviral immune responses.…”

Section: Discussionmentioning

confidence: 98%

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

et al. 2020

View full text Add to dashboard Cite

CD8+ T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8+ T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8+ T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8+ T cells. Mechanically, Mn2+ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8+ T cell differentiation, activation and NK cell activation, and increased memory CD8+ T cells. Combining Mn2+ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn2+ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.

show abstract

Section: Discussionmentioning

confidence: 98%

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

et al. 2020

View full text Add to dashboard Cite

show abstract

“… 24 Importantly, Mn 2+ was a potent innate immune stimulator by itself, inducing type I IFN and cytokine production in the absence of any infection. More recently, studies from Sohn’s lab and our lab demonstrated that Mn 2+ directly activates cGAS independent of DNA and triggers a distinct catalytic synthesis of 2′3′-cGAMP, 25 , 26 strengthening the potential applications of Mn 2+ as a novel STING agonist to boost immune responses.…”

Section: Introductionmentioning

confidence: 77%

“…It may not be surprising that Mn and cGAS-STING are involved in regulating adaptive immunity, given that the cGAS-STING pathway is important in the immunosurveillance of all aberrant cells, including infected, damaged, senesced, mutated, or dead cells, 47 and that Mn 2+ greatly sensitizes cGAS-STING 24 and/or directly activates cGAS. 25 , 26 Furthermore, it has been well established that type I IFNs bridge innate and adaptive immunity by promoting the maturation and activation of DCs for antigen presentation; stimulating TH1 responses, especially CTL activation; and enhancing the survival of memory T cells. 48 – 50 Accordingly, recent works have reported that various antitumor therapies depend on the activation of the cGAS-STING pathway 51 – 53 by promoting tumor-specific antigen presentation and CTL activation.…”

Section: Discussionmentioning

confidence: 99%

Manganese salts function as potent adjuvants

et al. 2021

View full text Add to dashboard Cite

Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn2+ is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn2+ alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2′3′-cGAMP. Herein, we found that Mn2+ strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4+/CD8+ T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.

show abstract

“… 43 In addition, Mn 2+ could also augment cGAS enzymatic activity by enhancing its sensitivity to low doses of dsDNA usually nonstimulatory, 163 or directly activate cGAS independent of dsDNA to synthesize cGAMP, 164 presumably through activating monomeric cGAS without dsDNA. 165 Notably, there is new evidence demonstrating that K + efflux might suppress cGAS activation in decreasing the type I interferon responses, 166 while the underlying mechanistic insights warrant further investigations. Interestingly, some copper (Cu 2+ ) complexes used in anticancer therapy inhibit topoisomerase 1 and 2, leading to DNA breaks and DNA fragments to activate cGAS signaling.…”

Section: Regulation Of Cgas Activation By Ionsmentioning

confidence: 99%

Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

Liu

2021

Sig Transduct Target Ther

105

View full text Add to dashboard Cite

Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special asymmetric cyclic-dinucleotide, 2′3′-cGAMP, as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory genes. Hyperactivation of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune therapy. On the other hand, inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune surveillance. Thus, cGAS activation is tightly controlled. In this review, we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation, including cGAS pre- and post-translational regulations, cGAS-binding proteins, and additional cGAS regulators such as ions and small molecules. We will also reveal the pathophysiological function of cGAS and its product cGAMP in human diseases. We hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.

show abstract

Allosteric coupling between Mn2+ and dsDNA controls the catalytic efficiency and fidelity of cGAS

Cited by 67 publications

References 42 publications

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

Manganese salts function as potent adjuvants

Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

Contact Info

Product

Resources

About