DSTYK phosphorylates STING at late endosomes to promote STING signaling DOI Creative Commons

Hao Dong,

Heng Zhang, Pu Song

и другие.

EMBO Reports, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Stimulator of interferon genes (STING) is essential for innate immune pathway activation in response to pathogenic DNA. Proper STING signaling requires translocation and phosphorylation. Here, we show that dual serine/threonine tyrosine protein kinase (DSTYK) directly phosphorylates Ser366 at late endosomes promote the signaling. We find TBK1 promotes post-Golgi trafficking via its activity, thereby enabling interaction between DSTYK STING. also demonstrate can both phosphorylation endosomes. Using an vivo Dstyk-knockout model, showed mice deficient reduced are more susceptible infection with a DNA virus. Together, reveal previously unknown cellular function phosphorylating our findings provide insights into mechanism

Язык: Английский

Mitochondrial DNA-triggered innate immune response: mechanisms and diseases DOI Creative Commons

Ming-Ming Hu,

Hong‐Bing Shu

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(12), С. 1403 - 1412

Опубликована: Ноя. 7, 2023

Abstract Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by cGAS-MITA/STING pathway, resulting in induced expression of type I interferon and other effector genes. These processes contribute to innate immune response viral infection factors. deregulation these causes autoimmune diseases, inflammatory metabolic disorders cancer. Therefore, pathway a potential target for intervention infectious, diseases as well In this review, we focus on mechanisms underlying mtDNA-triggered activation effects under various physiological pathological conditions, advances development drugs that cGAS MITA/STING.

Язык: Английский

Процитировано

57
A Bioactive Injectable Hydrogel Regulates Tumor Metastasis and Wound Healing for Melanoma via NIR‐Light Triggered Hyperthermia DOI Creative Commons
Xueyi Liu,

Meifang Shen,

Tiejun Bing

и другие.

Advanced Science, Год журнала: 2024, Номер 11(26)

Опубликована: Май 5, 2024

Abstract Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting high recurrence rates patients. Herein, a bioactive injectable hydrogel (BG‐Mn gel ) formed by crosslinking sodium alginate (SA) with manganese‐doped glass (BG‐Mn) is developed as versatile platform anti‐tumor immunotherapy postoperative The incorporation of Mn 2+ within (BG) can activate cGAS‐STING immune pathway to elicit robust response cancer immunotherapy. Furthermore, doping BG endows system excellent photothermal properties, hence facilitating STING activation reversing immune‐suppressive microenvironment. exhibits favorable angiogenic capacity tissue regenerative potential, promotes cell migration vitro. When combining BG‐Mn anti‐PD‐1 antibody (α‐PD‐1) melanoma, it shows enhanced long‐term memory response. Remarkably, upregulate expression genes related blood vessel formation promote skin regeneration when treating full‐thickness wounds. Overall, Gel serves an effective adjuvant therapy regulate

Язык: Английский

Процитировано

20
Regulation of cGAS–STING signalling and its diversity of cellular outcomes DOI
Zhengyin Zhang, Conggang Zhang

Nature reviews. Immunology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Язык: Английский

Процитировано

9
cGAS‐STING signaling in cell death: Mechanisms of action and implications in pathologies DOI Open Access
Yifan Xu, Chen Chen, Zhiyong Liao

и другие.

European Journal of Immunology, Год журнала: 2023, Номер 53(9)

Опубликована: Июль 9, 2023

Cyclic GMP-AMP synthase (cGAS) monitors dsDNA in the cytosol response to pathogenic invasion or tissue injury, initiating cGAS-STING signaling cascades that regulate various cellular physiologies, including IFN /cytokine production, autophagy, protein synthesis, metabolism, senescence, and distinct types of cell death. is crucial for host defense homeostasis; however, its dysfunction frequently leads infectious, autoimmune, inflammatory, degenerative, cancerous diseases. Our knowledge regarding relationships between death rapidly evolving, highlighting their essential roles pathogenesis disease progression. Nevertheless, direct control by signaling, rather than IFN/NF-κB-mediated transcriptional regulation, remains relatively unexplored. This review examines mechanistic interplays apoptosis, necroptosis, pyroptosis, ferroptosis, autophagic/lysosomal We will also discuss pathological implications human diseases, particularly autoimmunity, cancer, organ injury scenarios. hope this summary stimulate discussion further exploration complex life-or-death responses damage mediated signaling.

Язык: Английский

Процитировано

25
Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds DOI Creative Commons
Bao‐cun Zhang, Marlene Fyrstenberg Laursen, Lili Hu

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 29, 2024

Abstract The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly induction of interferon inflammatory cytokines. Here we report that cGAMP stimulation leads transient decline ER cholesterol levels, mediated Sterol O-Acyltransferase 1-dependent esterification. This facilitates membrane curvature trafficking Golgi. Notably, identify two cholesterol-binding motifs confirm their contribution ER-retention STING. Consequently, depletion intracellular levels enhances activation upon stimulation. In preclinical model, intratumorally administered therapy potentiated STING-dependent responses, which, combination with anti-PD-1 antibodies, promoted remission. Collectively, demonstrate sets threshold for through propose this could be exploited cancer immunotherapy.

Язык: Английский

Процитировано

17
Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing DOI Creative Commons
Qi Qu, Yan Chen, Yu Wang

и другие.

Nature, Год журнала: 2024, Номер unknown

Опубликована: Дек. 18, 2024

Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing1. However, the molecular details of how LCA activates AMPK induces these biological effects are unclear. Here we show that enhances activity sirtuins deacetylate subsequently inhibit vacuolar H+-ATPase (v-ATPase), which leads activation through lysosomal glucose-sensing pathway. Proteomics analyses proteins co-immunoprecipitated with sirtuin 1 (SIRT1) identified TUB-like 3 (TULP3), a sirtuin-interacting protein2, as receptor. In detail, LCA-bound TULP3 allosterically sirtuins, then V1E1 subunit v-ATPase on residues K52, K99 K191. Muscle-specific expression mutant (3KR), mimics deacetylated state, strongly rejuvenates muscles aged mice. nematodes flies, depends homologues tub-1 ktub, respectively, extend lifespan healthspan. Our study demonstrates TULP3–sirtuin–v-ATPase–AMPK pathway by reproduces benefits restriction. The mechanism underlying lithocholic recapitulates healthspan revealed involve TULP3, AMPK.

Язык: Английский

Процитировано

16
The activation of the adaptor protein STING depends on its interactions with the phospholipid PI4P DOI Open Access
Rutger D. Luteijn, Sypke R. van Terwisga, Jill E. Ver Eecke

и другие.

Science Signaling, Год журнала: 2024, Номер 17(827)

Опубликована: Март 12, 2024

Activation of the endoplasmic reticulum (ER)-resident adaptor protein STING, a component cytosolic DNA-sensing pathway, induces transcription genes encoding type I interferons (IFNs) and other proinflammatory factors. Because STING is activated at Golgi apparatus, control localization activation important in stimulating antiviral antitumor immune responses. Through genome-wide CRISPR interference screen, we found that required Golgi-resident ACBD3, which promotes generation phosphatidylinositol 4-phosphate (PI4P) trans-Golgi network, as well PI4P-associated proteins. Appropriate apparatus ACBD3 PI4P-generating kinase PI4KB. In contrast, was enhanced when lipid-shuttling OSBP, removes PI4P from inhibited by US Food Drug Administration-approved antifungal itraconazole. The increase abundance STING-activating phospholipids network resulted increased production IFN-β cytokines THP-1 cells. Furthermore, mutant could not bind to failed traffic ER response agonist, whereas forced relocalization PI4P-enriched areas elicited absence stimulation with agonist. Thus, critical for activation, manipulating may therapeutically modulate STING-dependent

Язык: Английский

Процитировано

15
AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine DOI Creative Commons
Mengqi Li, Yu Wang, Xiaoyan Wei

и другие.

Cell Research, Год журнала: 2024, Номер 34(10), С. 683 - 706

Опубликована: Июнь 19, 2024

Abstract The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation cope with decreased blood levels and the consequent decline in oxidation. AMP-activated protein kinase (AMPK) plays crucial roles this adaptation. However, underlying mechanism not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which identify as new substrate AMPK activated low glucose, required for glucose-promoted glutaminolysis. phosphorylates PDZD8 at threonine 527 (T527) promotes interaction activation glutaminase 1 (GLS1), rate-limiting enzyme In vivo, AMPK-PDZD8-GLS1 axis enhancement glutaminolysis tested skeletal muscle tissues, occurs earlier than increase fatty acid during fasting. enhanced also observed macrophages or under acute lipopolysaccharide (LPS) treatment. Consistent requirement heightened glutaminolysis, PDZD8-T527A mutation dampens secretion pro-inflammatory cytokines mice treated LPS. Together, have revealed an ahead increased shortage.

Язык: Английский

Процитировано

13
Targeting GOLPH3L improves glioblastoma radiotherapy by regulating STING-NLRP3–mediated tumor immune microenvironment reprogramming DOI
Shuo Sun,

Shiyu Qian,

Ran Wang

и другие.

Science Translational Medicine, Год журнала: 2025, Номер 17(788)

Опубликована: Март 5, 2025

Radiotherapy (RT) has been the standard-of-care treatment for patients with glioblastoma (GBM); however, clinical effectiveness is hindered by therapeutic resistance. Here, we demonstrated that tumor immune microenvironment (TIME) exhibited immunosuppressive properties and high expression of Golgi phosphoprotein 3 like (GOLPH3L) in RT-resistant GBM. Our study showed GOLPH3L interacted stimulator interferon genes (STING) at aspartic acid residue 184 after RT, leading to coat protein complex II-mediated retrograde transport STING from endoplasmic reticulum. This suppressed STING-NOD-like receptor thermal domain associated (NLRP3)-mediated pyroptosis, resulting suppressive TIME, driving GBM resistance RT. Genetic ablation cells augmented antitumor immunity overcame Moreover, have identified a small molecular inhibitor GOLPH3L, vitamin B5 calcium (VB5), which improved efficacy RT checkpoint blockade inducing robust response mouse models. Clinically, treated VB5 responses Thus, reprogramming TIME targeting may offer potential opportunity improve

Язык: Английский

Процитировано

2
Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities DOI
Alicia Llorente Lope, Gurpreet K. Arora, Rabi Murad

и другие.

Nature reviews. Cancer, Год журнала: 2025, Номер unknown

Опубликована: Апрель 3, 2025

Язык: Английский

Процитировано

1