TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer DOI Creative Commons
Hongwei Lv,

Qianni Zong,

Cian Chen

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 4, 2024

Abstract Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway vital for anti-tumor immunity, but its role in vasculature unclear. Herein, using preclinical liver cancer models Cgas / Sting -deficient male mice, we report that the interdependence between cGAS and host STING mediates immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates expression produces cGAMP. Subsequently, cGAMP transported via LRRC8C channels activate endothelial cells, enhancing recruitment transendothelial migration lymphocytes. In vivo studies mice also reveal administration vitamin C, promising anti-cancer agent, stimulates activity, induces enhances efficacy anti-PD-L1 therapy alone or combination with IL-2. Our findings elucidate crosstalk cells microenvironment, providing strategies combinational cancer.

Language: Английский

LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP DOI Creative Commons
Lauren J. Lahey,

Rachel E. Mardjuki,

Xianlan Wen

et al.

Molecular Cell, Journal Year: 2020, Volume and Issue: 80(4), P. 578 - 591.e5

Published: Nov. 1, 2020

Language: Английский

Citations

146
Old dogs, new trick: classic cancer therapies activate cGAS DOI Creative Commons
Seoyun Yum, Minghao Li, Zhijian J. Chen

et al.

Cell Research, Journal Year: 2020, Volume and Issue: 30(8), P. 639 - 648

Published: June 15, 2020

The discovery of cancer immune surveillance and immunotherapy has opened up a new era treatment. Immunotherapies modulate patient's system to specifically eliminate cells; thus, it is considered very different approach from classic therapies that usually induce DNA damage cause cell death in cell-intrinsic manner. However, recent studies have revealed such as radiotherapy chemotherapy also elicit antitumor immunity, which plays an essential role their therapeutic efficacy. cytosolic sensor cyclic GMP-AMP synthase (cGAS) the downstream effector Stimulator Interferon Genes (STING) been determined be critical for this interplay. Here, we review roles cGAS-STING pathway during tumorigenesis, surveillance, therapies. We highlight responses through cGAS activation.

Language: Английский

Citations

144
Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice DOI
Xiaochun Xie,

Guanqin Ma,

Xiaohong Li

et al.

Nature Aging, Journal Year: 2023, Volume and Issue: 3(2), P. 202 - 212

Published: Jan. 9, 2023

Language: Английский

Citations

120
Delivery of STING agonists for adjuvanting subunit vaccines DOI Creative Commons
Simon Van Herck, Bing Feng, Li Tang

et al.

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 179, P. 114020 - 114020

Published: Oct. 29, 2021

Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy Recently discovered cyclic GMP-AMP synthase-stimulator interferon genes (cGAS-STING) pathway has attracted much attention it a key mediator for modulating immune responses. Vaccines adjuvanted with STING are found mediate robust defense against infections cancer. In this review, we first discuss mechanisms context vaccination. Next, present recent progress novel agonist discovery delivery strategies. We next highlight work optimizing while minimizing toxicity agonist-assisted vaccines protection infectious diseases or treatment Finally, share our perspectives current issues future directions further developing adjuvanting

Language: Английский

Citations

117
Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer DOI Creative Commons
Zikun Ma, Xiangdong Li, Yize Mao

et al.

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(12), P. 1550 - 1565.e7

Published: Dec. 1, 2022

Language: Английский

Citations

117
The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity DOI Creative Commons

Nanxin Liu,

Xiaoxiao Pang, Hua Zhang

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 13, 2022

Cyclic guanosine monophosphate (GMP)-adenosine (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components innate immune system, and their study has become a research hotspot in recent years. Many biochemical structural studies that have collectively elucidated mechanism activation cGAS-STING pathway atomic resolution provided insights into roles immunity clues to origin evolution modern signaling pathway. The been identified protect host against viral infection. After detecting dsDNA, cGAS synthesizes second messenger activate STING, eliciting antiviral responses by promoting expression interferons (IFNs) hundreds IFN-stimulated (ISGs). Recently, also found be involved response bacterial infections, including pneumonia, melioidosis, tuberculosis, sepsis. However, compared its functions infection, infection is more complex diverse since protective detrimental effects type I IFN (IFN-I) on depend species mode. Besides, STING can affect prognosis through other mechanisms different independent IFN-I response. Interestingly, core protein mammalian defense suggesting this widespread may originated bacteria. Here, we review findings related structures major molecules various infections immunity, which pave way for development new antibacterial drugs specifically kill bacteria without harmful host.

Language: Английский

Citations

101
Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy DOI Creative Commons
Zili Zhang, Haifeng Zhou, Xiaohu Ouyang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 23, 2022

Since the discovery of Stimulator Interferon Genes (STING) as an important pivot for cytosolic DNA sensation and interferon (IFN) induction, intensive efforts have been endeavored to clarify molecular mechanism its activation, physiological function a ubiquitously expressed protein, explore potential therapeutic target in wide range immune-related diseases. With orthodox ligand 2'3'-cyclic GMP-AMP (2'3'-cGAMP) upstream sensor 2'3'-cGAMP synthase (cGAS) be found, STING acquires central functionality best-studied signaling cascade, namely cGAS-STING-IFN pathway. However, recently updated research through structural research, genetic screening, biochemical assay greatly extends current knowledge biology. A second pocket was discovered transmembrane domain synthetic agonist. On downstream outputs, accumulating studies sketch primordial multifaceted roles beyond cytokine-inducing function, such autophagy, cell death, metabolic modulation, endoplasmic reticulum (ER) stress, RNA virus restriction. Furthermore, with expansion interactome, details trafficking also get clearer. After retrospecting brief history viral interference milestone events since STING, we present vivid panorama biology taking into account information, especially versatile outputs functions IFN induction. We summarize pathogenesis various diseases highlight development small-molecular compounds targeting disease treatment combination latest research. Finally, discuss open questions imperative answer.

Language: Английский

Citations

93
NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking DOI Creative Commons
Lulu Zhang,

Xubiao Wei,

Zhimeng Wang

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112185 - 112185

Published: Feb. 28, 2023

It is widely known that stimulator of interferon genes (STING) can trigger nuclear factor κB (NF-κB) signaling. However, whether and how the NF-κB pathway affects STING signaling remains largely unclear. Here, we report Toll-like receptor (TLR)-, interleukin-1 (IL-1R)-, tumor necrosis (TNFR)-, growth (GF-R)-, protein kinase C (PKC)-mediated activation dramatically enhances STING-mediated immune responses. Mechanistically, find interacts with microtubules, which plays a crucial role in intracellular trafficking. We further uncover canonical induces microtubule depolymerization, inhibits trafficking to lysosomes for degradation. This leads increased levels activated persist longer period time. The synergy between triggers cascade-amplified response robust host antiviral defense. In addition, observe several gain-of-function mutations abolish microtubule-STING interaction cause abnormal ligand-independent autoactivation. Collectively, our data demonstrate by regulating microtubule-mediated

Language: Английский

Citations

87
Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS–cGAMP–STING Pathway DOI Open Access
Christopher Ritchie,

Jacqueline A. Carozza,

Lingyin Li

et al.

Annual Review of Biochemistry, Journal Year: 2022, Volume and Issue: 91(1), P. 599 - 628

Published: March 15, 2022

In the decade since discovery of innate immune cyclic GMP-AMP synthase (cGAS)-2'3'-cyclic (cGAMP)-stimulator interferon genes (STING) pathway, its proper activation and dysregulation have been rapidly implicated in many aspects human disease. Understanding biochemical, cellular, regulatory mechanisms this pathway is critical to developing therapeutic strategies that either harness it boost defense or inhibit prevent unwanted inflammation. review, we first discuss how second messenger cGAMP synthesized by cGAS response double-stranded DNA cGAMP's subsequent cell-type-dependent STING signaling cascades with differential physiological consequences. We then review as an immunotransmitter mediates tightly controlled cell-cell communication being exported from producing cells imported into responding via cell-type-specific transporters. Finally, which thecGAS-cGAMP-STING responds different sources mislocalized pathogen defense, cancer, autoimmune diseases.

Language: Английский

Citations

82
The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING–p53 signaling DOI
Axel R. Concepcion, Larry E. Wagner, Jingjie Zhu

et al.

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(2), P. 287 - 302

Published: Feb. 1, 2022

Language: Английский

Citations

81