Activation of STING by targeting a pocket in the transmembrane domain

Lu, Defen; Shang, Guijun; Li, Jie; Lu, Yong; Bai, Xiao Chen; Zhang, Xuewu

doi:10.1038/s41586-022-04559-7

Cited by 96 publications

(85 citation statements)

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“…In contrast, backbone interactions between two neighboring LBDα2–α3 loops were seen in the human LBD/cGAMP crystal lattice ( 14 ). A recent structural study of the human STING/cGAMP/compound C53 ternary complex shows that both the LBD and TM domain contribute to the oligomer formation ( 49 ) ( Figure 6 ). In this structure, the adjacent LBD interactions involving backbone interaction occur at the LBDα2–α3 loop consisting of residues Q273, Y274, and S275, which is consistent with the crystal structure observation ( Figure 6B ).…”

Section: Ligand Recognition and Signal Transductionmentioning

confidence: 99%

Activation of STING Based on Its Structural Features

et al. 2022

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The cGAS-cGAMP-STING pathway is an important innate immune signaling cascade responsible for the sensing of abnormal cytosolic double-stranded DNA (dsDNA), which is a hallmark of infection or cancers. Recently, tremendous progress has been made in the understanding of the STING activation mechanism from various aspects. In this review, the molecular mechanism of activation of STING protein based on its structural features is briefly discussed. The underlying molecular mechanism of STING activation will enable us to develop novel therapeutics to treat STING-associated diseases and understand how STING has evolved to eliminate infection and maintain immune homeostasis in innate immunity.

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Section: Ligand Recognition and Signal Transductionmentioning

confidence: 99%

Activation of STING Based on Its Structural Features

et al. 2022

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“…4e). Previously, structures of a TIR-STING homologue from the oyster Crassostrea gigas and the human transmembrane domain-containing STING in inactive states revealed a twisted linker sequence that connects the effector domain to the STING domain located across the dimeric interface 4,5,13 (Extended Data Fig. 4e).…”

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confidence: 99%

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Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes [1][2][3][4] . Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide [4][5][6][7][8][9][10][11][12][13] , but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)-STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon.

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confidence: 99%

“…STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.Activation of STING signalling results in assembly of oligomeric filament structures that have been observed in both human innate immunity and bacterial antiphage defence [4][5][6][7][8][9][10][11][12][13] . Key early findings supporting STING oligomerization as a required step of activation include observation of STING puncta formation in cells 9 , electrophoresis analysis of STING multimeric complexes 10,11 and artificial activation of STING on fusion to multimerization domains 12 .…”

mentioning

confidence: 99%

“…Activation of STING signalling results in assembly of oligomeric filament structures that have been observed in both human innate immunity and bacterial antiphage defence [4][5][6][7][8][9][10][11][12][13] . Key early findings supporting STING oligomerization as a required step of activation include observation of STING puncta formation in cells 9 , electrophoresis analysis of STING multimeric complexes 10,11 and artificial activation of STING on fusion to multimerization domains 12 .…”

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Cryo-EM structure of an active bacterial TIR–STING filament complex

Morehouse

Yip

Keszei

et al. 2022

Nature

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Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes1–4. Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide4–13, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)–STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR–STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals5. The active bacterial TIR–STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD+ hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.

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Simultaneous Activation of Pyroptosis and cGAS‐STING Pathway with Epigenetic/ Photodynamic Nanotheranostic for Enhanced Tumor Photoimmunotherapy

Ding,

Liu,

et al. 2023

Advanced Materials

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Promoting innate immunity through pyroptosis induction or cGAS‐STING pathway activation has emerged as a potent approach to counteract the immunosuppressive tumor microenvironment and elicit systemic antitumor immunity. However, current pyroptosis inducers and STING agonists often suffer from limitations including instability, unpredictable side effects, or inadequate intracellular expression of gasdermin and STING. Here, a tumor‐specific nanotheranostic platform that combines photodynamic therapy (PDT) with epigenetic therapy to simultaneously activate pyroptosis and the cGAS‐STING pathway in a light‐controlled manner is constructed. This approach involves the development of oxidation‐sensitive nanoparticles (NP1) loaded with the photosensitizer TBE, along with decitabine liposomes (NP2). NP2 enables the restoration of STING and GSDME expression, while NP1‐mediated PDT facilitates the release of DNA fragments from damaged mitochondria to potentiate the cGAS‐STING pathway, and promotes the activation of caspase‐3 to cleave the upregulated GSDME into pore‐forming GSDME‐N terminal. Subsequently, the released inflammatory cytokines facilitate the maturation of antigen‐presentation cells, triggering T cell‐mediated antitumor immunity. Overall, this study presents an elaborate strategy for simultaneous photoactivation of pyroptosis and the cGAS‐STING pathway, enabling targeted photoimmunotherapy in immunotolerant tumors. This innovative approach holds significant promise in overcoming the limitations associated with existing therapeutic modalities and represents a valuable avenue for future clinical applications.This article is protected by copyright. All rights reserved

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Activation of STING by targeting a pocket in the transmembrane domain

Cited by 96 publications

References 44 publications

Activation of STING Based on Its Structural Features

Activation of STING Based on Its Structural Features

Cryo-EM structure of an active bacterial TIR–STING filament complex

Simultaneous Activation of Pyroptosis and cGAS‐STING Pathway with Epigenetic/ Photodynamic Nanotheranostic for Enhanced Tumor Photoimmunotherapy

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