STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage

Wang, Chenyao; Jing, Nan; Holvey-Bates, Elise; Chen, Xing; Wightman, Samantha M.; Latif, Muhammad-Bilal; Zhao, Junjie; Li, Xiaoxia; Sen, Ganes C.; Stark, George R.; Wang, Yuxin

doi:10.1073/pnas.2216953120

Cited by 7 publications

(3 citation statements)

References 69 publications

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“…Second, STAT2 might co-orchestrate together with IRF9, and to a lesser extent STAT1, the expression of a subset of interferon-related DNA damage signature genes that have been previously associated with resistance to chemotherapy and radiotherapy [67][68][69][70]. Third, STAT2-dependent inhibition of STING promoted chemotherapy resistance and tumor progression in a study reporting a significant association between high STAT2 tumor levels and shorter overall survival in patients with lung adenocarcinomas [71]. The fact that Apc Min/+ WT tumoroids were resistant to anti-cancer drugs provides circumstantial evidence for the second and third scenarios, as well.…”

Section: Discussionmentioning

confidence: 98%

STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs

Chiriac,

Hracsko,

Becker

et al. 2023

Cancers

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Colorectal cancer (CRC) is a significant socioeconomic burden in modern society and is accountable for millions of premature deaths each year. The role of signal transducer and activator of transcription 2 (STAT2)-dependent signaling in this context is not yet fully understood, and no therapies targeting this pathway are currently being pursued. We investigated the role of STAT2 in CRC using experimental mouse models coupled with RNA-sequencing (RNA-Seq) data and functional assays with anti-cancer agents in three-dimensional tumoroids. Stat2−/− mice showed greater resistance to the development of CRC in both inflammation-driven and inflammation-independent experimental CRC models. In ex vivo studies, tumoroids derived from Stat2−/− mice with the multiple intestinal neoplasia (Min) mutant allele of the adenomatous polyposis coli (Apc) locus exhibited delayed growth, were overall smaller and more differentiated as compared with tumoroids from ApcMin/+ wildtype (WT) mice. Notably, tumoroids from ApcMin/+ Stat2−/− mice were more susceptible to anti-cancer agents inducing cell death by different mechanisms. Our findings clearly indicated that STAT2 promotes CRC and suggested that interventions targeting STAT2-dependent signals might become an attractive therapeutic option for patients with CRC.

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Section: Discussionmentioning

confidence: 98%

STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs

Chiriac,

Hracsko,

Becker

et al. 2023

Cancers

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“…Patients with cancers that express rich STAT2 have a more impaired prognosis than those expressing poor STAT2 [ 80 ]. Recently, the mechanism underlying this phenomenon was partially unveiled [ 81 ]. STAT2 binds to STING, which localizes near the ER and prohibits the translocation of STING into the cytosol upon DNA damage-inducing agents.…”

Section: Cirt Activation Of Anti-cancer Immunitymentioning

confidence: 99%

Carbon Ion Irradiation Activates Anti-Cancer Immunity

Sudo,

Tsutsui,

Fujimoto

2024

IJMS

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Carbon ion beams have the unique property of higher linear energy transfer, which causes clustered damage of DNA, impacting the cell repair system. This sometimes triggers apoptosis and the release in the cytoplasm of damaged DNA, leading to type I interferon (IFN) secretion via the activation of the cyclic GMP–AMP synthase-stimulator of interferon genes pathway. Dendritic cells phagocytize dead cancer cells and damaged DNA derived from injured cancer cells, which together activate dendritic cells to present cancer-derived antigens to antigen-specific T cells in the lymph nodes. Thus, carbon ion radiation therapy (CIRT) activates anti-cancer immunity. However, cancer is protected by the tumor microenvironment (TME), which consists of pro-cancerous immune cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The TME is too robust to be destroyed by the CIRT-mediated anti-cancer immunity. Various modalities targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages have been developed. Preclinical studies have shown that CIRT-mediated anti-cancer immunity exerts its effects in the presence of these modalities. In this review article, we provide an overview of CIRT-mediated anti-cancer immunity, with a particular focus on recently identified means of targeting the TME.

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“…In the other branch, STING travels from ERGIC to autophagophores and then to the autophagosomes which fuse with the lysosomes to form the autolysosomes 13,23 . The transit of STING from one compartment to the next requires participation of specific chaperone proteins 13,20,24–31 …”

Section: Introductionmentioning

confidence: 99%

Interferon induction by STING requires its translocation to the late endosomes

Wang,

Sharma,

Kessler

et al. 2023

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To combat microbial infections, mammalian cells use a variety of innate immune response pathways to induce synthesis of anti‐microbial proteins. The cGAS/STING pathway recognizes cytoplasmic viral or cellular DNA to elicit signals that lead to type I interferon and other cytokine synthesis. cGAMP, synthesized by DNA‐activated cGAS, activates the ER‐associated protein, STING, which oligomerizes and translocates to other intracellular membrane compartments to trigger different branches of signaling. We have reported that, in the ER, EGFR‐mediated phosphorylation of Tyr245 of STING is required for its transit to the late endosomes, where it recruits and activates the transcription factor IRF3 required for IFN induction. In the current study, we inquired whether STING Tyr245 phosphorylation per se or STING's location in the late endosomes was critical for its ability to recruit IRF3 and induce IFN. Using pharmacological inhibitors or genetic ablation of proteins that are essential for specific steps of STING trafficking, we demonstrated that the presence of STING in the late endosomal membranes, even without Tyr245 phosphorylation, was sufficient for IRF3‐mediated IFN induction.

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STAT2 hinders STING intracellular trafficking and reshapes its activation in response to DNA damage

Cited by 7 publications

References 69 publications

STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs

STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs

Carbon Ion Irradiation Activates Anti-Cancer Immunity

Interferon induction by STING requires its translocation to the late endosomes

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