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Phase separation in cGAS-STING signaling

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Frontiers of Medicine 2023年第5期17卷 855-866页

作者： Quanjin Li Pu Gao CAS Key Laboratory of Infection and Immunity National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China University of Chinese Academy of Sciences Beijing100049China

Biomolecular condensates formed by phase separation are widespread and play critical roles in many physiological and pathological processes.cGAS-STING signaling functions to detect aberrant DNA signals to initiate anti-infection defense and antitumor immunity.At the same time,cGAS-STING signaling must be carefully regulated to maintain immune homeostasis.Interestingly,exciting recent studies have reported that biomolecular phase separation exists and plays important roles in different steps of cGAS-STING signaling,including cGAS condensates,STING condensates,and IRF3 condensates.In addition,several intracellular and extracellular factors have been proposed to modulate the condensates in cGAS-STING signaling.These studies reveal novel activation and regulation mechanisms of cGAS-STING signaling and provide new opportunities for drug discovery.Here,we summarize recent advances in the phase separation of cGAS-STING signaling and the development of potential drugs targeting these innate immune condensates.

关键词： biomolecular condensates phase separation cGAS-STING pathway cGAS STING cGAMP interferon

The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

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Acta Pharmaceutica Sinica B 2022年第1期12卷 50-75页

作者： Patrick Kwabena Oduro Xianxian Zheng Jinna Wei Yanze Yang Yuefei Wang Han Zhang Erwei Liu Xiumei Gao Mei Du Qilong Wang Institute of Traditional Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China State Key Laboratory of Component-Based Chinese Medicine Ministry of EducationTianjin 301617China Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology School of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure,myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns(mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism.Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.

关键词： STING cGAS Cardiovascular diseases Metabolic diseases Damage-associated molecular patterns Inflammation ER stress Mitochondria

cGAS guards against chromosome endto-end fusions during mitosis and facilitates replicative senescence

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Protein & Cell 2022年第1期13卷 47-64页

作者： Xiaocui Li Xiaojuan Li Chen Xie Sihui Cai Mengqiu Li Heping Jin Shu Wu Jun Cui Haiying Liu Yong Zhao MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yatsen UniversityGuangzhou 510006China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510006China Department of Biochemistry School of Life SciencesSun Yat-sen UniversityGuangzhou 510006China

As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

关键词： cGAS telomeres chromosome end-toend fusion DNA damage response non-homologous end joining mitosis genome stability

Nuclear cGAS: sequestration and beyond

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Protein & Cell 2022年第2期13卷 90-101页

作者： Juli Bai Feng Liu Departments of Pharmacology University of Texas Health at San AntonioSan AntonioTXUSA National Clinical Research Center for Metabolic Diseases Metabolic Syndrome Research CenterKey Laboratory of Diabetes ImmunologyMinistry of Educationand Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangsha 410011China

The cyclic GMP-AMP(cGAMP)synthase(cGAS)has been identified as a cytosolic double stranded DNA sensor that plays a pivotal role in the type I interferon and inflammation responses via the STING-dependent signaling pathway.In the past several years,a growing body of evidence has revealed that cGAS is also localized in the nucleus where it is associated with distinct nuclear substructures such as nucleosomes,DNA replication forks,the double-stranded breaks,and centromeres,suggesting that cGAS may have other functions in addition to its role in DNA sensing.However,while the innate immune function of cGAS is well established,the non-canonical nuclear function of cGAS remains poorly understood.Here,we review our current understanding of the complex nature of nuclear cGAS and point to open questions on the novel roles and the mechanisms of action of this protein as a key regulator of cell nuclear function,beyond its well-established role in dsDNA sensing and innate immune response.

关键词： cGAS STING innate immunity nuclear translocation DNA damage repair micronuclei

Mitotic inactivation of the cGAS-MITA/STING pathways

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Journal of Molecular Cell Biology 2021年第10期13卷 721-727页

作者： Li Zhong Hong-Bing Shu Department of Infectious Diseases Frontier Science Center for Immunology and MetabolismMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan UniversityResearch Unit of Innate Immune and Inflammatory Diseases of the Chinese Academy of Medical SciencesWuhan 430071China

The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-mediator of interferon response factor 3 acti-vation/stimulator of interferon genes(MITA/STING)axis has emerged as a major pathway,which senses microbial or mislocated cellular DNA in the cytosol to trigger innate immune responses.cGAS senses cytosolic DNA without a preference of self-or nonself-DNA.How the cGAS-MITA/STING axis is inactivated upon nuclear envelope breakdown(NEBD)at mitotic entry in vertebrate cells to avoid self-DNA sensing remains unclear until very recently.In this review,we summarize the recent advances on how cGAS responds to chromosomes upon NEBD and the mechanisms involved in the inactivation of the cGAS-MITA/STING pathways in mitosis.

关键词： cGAS MITA STING mitosis innate immune response DNA

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

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1483-1497页

作者： Le Yu Pengda Liu Lineberger Comprehensive Cancer Center The University of North Carolina at Chapel HillChapel HillNCUSA Department of Biochemistry and Biophysics The University of North Carolina at Chapel HillChapel HillNCUSA

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.

关键词： diseases function cGAS

cGAS-STING signaling and function in metabolism and kidney diseases

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Journal of Molecular Cell Biology 2021年第10期13卷 728-738页

作者： Juli Bai Feng Liu Department of Pharmacology University of Texas Health at San AntonioSan AntonioTX 78229USA National Clinical Research Center for Metabolic Diseases Metabolic Syndrome Research CenterKey Laboratory of Diabetes ImmunologyMinistry of Educationand Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangsha 410011China

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway senses the presence of cytosolic DNA and,in turn,triggers downstream signaling to induce the expression of inflammatory and type I interferon genes in immune cells.Whereas the innate immune function of the cGAS-STING pathway is well studied over the past years,emerging evidence suggests that this signaling pathway may have additional functions beyond innate immune surveillance.Consistent with this notion,dysregulation of the cGAS-STING signaling pathway in adipocytes,hepatocytes,and renal proximal tubule epithelial cells are associated with metabolic dysfunction,impaired energy homeostasis,and kidney diseases.In this review,we summarize current understanding of the cGAS-STING pathway in several metabolic diseases such as obesity,insulin resistance,alcoholic and nonalcoholic fatty liver diseases,as well as acute kidney injury and chronic kidney disease.We also review the interaction between the cGAS-STING pathway and lipid metabolism.Lastly,we discuss potential mechanisms by which cGAS-STING signaling regulates metabolism and point toward future avenues of research targeting the cGAS-STING pathway as possible means to treat common metabolic disorders.

关键词： cGAS STING obesity NAFLD NASH AKI CDK

Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response

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Protein & Cell 2020年第8期11卷 584-599页

作者： Mi Li Hong-Bing Shu Department of Infectious Diseases Frontier Science Center for Immunology and MetabolismMedical Research InstituteZhongnan Hospital of Wuhan UniversityCollege of Life SciencesWuhan UniversityWuhan 430071China

The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosollc DNA derived from microbial pathogens or mls-located cellular DNA.Upon DNA binding,cGAS utilizes GTP and ATP as substrates to synthesize cGAMP,leading to MITA-mediated innate immune response.In this study,we identified the phosphatase PPP6C as a negative regulator of cGASmediated innate immune response.PPP6C is constitutively associated with cGAS in un-stimulated cells.DNA virus infection causes rapid disassociation of PPP6C from cGAS,resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket.Mutation of this eerine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection.In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity.PPP6Cdeficiency promotes innate immune response to DNA virus in various cells.Our findings suggest that PPP6Cmediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response,which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.

关键词： DNA virus PPP6C cGAS innate immune response phosphorylation substrate binding

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

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Acta Pharmaceutica Sinica B 2020年第12期10卷 2272-2298页

作者： Chunyong Ding Zilan Song Ancheng Shen Tingting Chen Ao Zhang Research Laboratory of Medicinal Chemical Biology&Frontiers on Drug Discovery(RLMCBFDD) School of PharmacyShanghai Jiao Tong UniversityShanghai 200240China CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica(SIMM)Chinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China

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

关键词： mmunotherapy Anti-tumor cGAS STING TBK1 Small molecule modulators