Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity

Immunity, Journal Year: 2020, Volume and Issue: 52(5), P. 767 - 781.e6

Published: April 10, 2020

Language: Английский

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Mn2+ Directly Activates cGAS and Structural Analysis Suggests Mn2+ Induces a Noncanonical Catalytic Synthesis of 2′3′-cGAMP

Cell Reports, Journal Year: 2020, Volume and Issue: 32(7), P. 108053 - 108053

Published: Aug. 1, 2020

DNA binding allosterically activates the cytosolic sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2′3′-cGAMP, using Mg2+ as metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found Mn2+ potentiates activation, but underlying mechanism remains unclear. Here, we report directly cGAS. Structural analysis reveals Mn2+-activated undergoes globally similar conformational changes DNA-activated forms a unique η1 helix widen catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in cGAS, linear intermediates pppGpG pGpA take an inverted orientation active suggesting noncanonical accelerated cyclization without flip-over. Moreover, unlike octahedral coordination around Mg2+, are coordinated by triphosphate moiety of substrate, independent triad residues. Our findings thus uncover activator initiates 2′3′-cGAMP

Language: Английский

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Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway

Acta Pharmaceutica Sinica B, Journal Year: 2020, Volume and Issue: 10(12), P. 2272 - 2298

Published: March 13, 2020

Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, blockade approach has achieved great clinic success as evidenced several U.S. Food Drug Administration (FDA)-approved anti-programmed death 1/ligand 1 or anti-cytotoxic lymphocyte associated protein 4 antibodies. However, majority of low clinical response rates these ICIs due poor tumor immunogenicity. Indeed, cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator interferon genes‒TANK-binding kinase (cGAS‒STING‒TBK1) axis is now appreciated major signaling pathway in innate across different species. Aberrant this closely linked multiple diseases, auto-inflammation, virus infection cancers. In perspective, we provide an updated review on latest progress development small molecule modulators targeting cGAS‒STING‒TBK1 their preclinical use a new stimulatory therapy. Meanwhile, highlights candidates, limitations challenges, well future directions field are also discussed. Further, potential therapeutic for indications discussed well.

Language: Английский

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Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 28, 2021

Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that decline of physical function often initiates by cell senescence organ ageing. Epigenetic dynamics immunometabolic reprogramming link to alterations cellular response intrinsic extrinsic stimuli, representing current hotspots as they not only (re-)shape individual identity, but also involve fate decision. This review focuses on present findings emerging concepts epigenetic, inflammatory, metabolic regulations consequences process. Potential therapeutic interventions targeting regulatory mechanisms, using state-of-the-art techniques are discussed.

Language: Английский

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Mechanisms and Regulation of Cellular Senescence

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 13173 - 13173

Published: Dec. 6, 2021

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete range pro-inflammatory proteolytic factors as part the senescence-associated secretory phenotype. There are different types senescent cells, can be induced response to many DNA damage signals. Senescent accumulate tissues organs where they have distinct physiological pathological functions. Despite this diversity, all must able survive nondividing while protecting themselves from positive feedback loops linked constant activation response. This capacity requires changes core cellular programs. Understanding how cell undergo extensive their transcriptional programs, metabolism, heterochromatin patterns, structures induce common is crucial preventing cancer development/progression improving health during aging. In review, we discuss continuously evolve after initial highlight unifying features that define state.

Language: Английский

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