An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP

Li, Xiaobo; Zhu, Yuanyuan; Zhang, Xiao; An, Xiang; Weng, Mingjiao; Shi, Jiaqi; Wang, Song; Liu, Caiqi; Luo, Sai; Zheng, Tongsen

doi:10.1172/jci144339

Cited by 20 publications

(29 citation statements)

References 31 publications

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“…Therefore, antiviral immune responses can be significantly enhanced by targeting extracellular ENPP1 expression or enhancing the levels of these cGAMP transporters upon viral infection. Surprisingly, recent studies have found that plasmatic membrane STING (pmSTING), an alternatively spliced STING isoform, directly senses extracellular cGAMP to mediate TBK1-mediated antiviral immunity ( Li et al., 2022 ). Furthermore, STING restricts HSV-1 infection independently of IFN signaling ( Wu et al., 2020 ), although the exact mechanism remains unclear.…”

Section: Regulation Of Cgas/sting Signalingmentioning

confidence: 99%

Regulation of cGAS/STING signaling and corresponding immune escape strategies of viruses

Ding

2022

Front. Cell. Infect. Microbiol.

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Innate immunity is the first line of defense against invading external pathogens, and pattern recognition receptors (PRRs) are the key receptors that mediate the innate immune response. Nowadays, there are various PRRs in cells that can activate the innate immune response by recognizing pathogen-related molecular patterns (PAMPs). The DNA sensor cGAS, which belongs to the PRRs, plays a crucial role in innate immunity. cGAS detects both foreign and host DNA and generates a second-messenger cGAMP to mediate stimulator of interferon gene (STING)-dependent antiviral responses, thereby exerting an antiviral immune response. However, the process of cGAS/STING signaling is regulated by a wide range of factors. Multiple studies have shown that viruses directly target signal transduction proteins in the cGAS/STING signaling through viral surface proteins to impede innate immunity. It is noteworthy that the virus utilizes these cGAS/STING signaling regulators to evade immune surveillance. Thus, this paper mainly summarized the regulatory mechanism of the cGAS/STING signaling pathway and the immune escape mechanism of the corresponding virus, intending to provide targeted immunotherapy ideas for dealing with specific viral infections in the future.

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Section: Regulation Of Cgas/sting Signalingmentioning

confidence: 99%

Regulation of cGAS/STING signaling and corresponding immune escape strategies of viruses

Ding

2022

Front. Cell. Infect. Microbiol.

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“…cGAMP can be also released by tumor cells and activate neighboring cells following entry via bidirectional transporters like LRRC8A and LRRC8C/E heteromeric channels 16 , 30 . Additional CDN transporters have been identified 14 , 15 and there is also evidence for the expression of an alternatively spliced STING isoform in the plasma cell membrane which can initiate immune responses by directly sensing extracellular cGAMP 17 . The expression of such transporters may vary among cell types and thus account for differential responses.…”

Section: Discussionmentioning

confidence: 99%

“…Without use of transfection reagents, the cellular uptake of exogenous cGAMP and similar CDN STING ligands varies between cell types, and SLC19A1 and LRRC8A have been identified as cell type-specific transporters of CDN across cell membranes 14 – 16 . Furthermore, an alternatively spliced STING isoform localized in the cytoplasmic membrane was recently shown to directly sense extracellular cGAMP 17 . Taken together, these cell type-specific variables add to the complexity when considering the use of cGAMP and related CDN as adjuvants in cancer therapy 18 .…”

Section: Introductionmentioning

confidence: 99%

Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes

Kabelitz

Zarobkiewicz

Heib

et al. 2022

Sci Rep

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The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway is a cytosolic sensor of microbial and host-derived DNA and plays a key role in innate immunity. Activation of STING by cyclic dinucleotide (CDN) ligands in human monocytes induces a type I interferon response and production of pro-inflammatory cytokines associated with the induction of massive cell death. In this study we have re-evaluated the effect of signal strength of STING activation on the cytokine plasticity of human monocytes. CDN (2′3′c-GAMP) and non-CDN (diABZI, MSA-2) STING ligands in the range of EC50 concentrations (15 μM 2′3′c-GAMP, 100 nM diABZI, 25 μM MSA-2) induced IFN-β, IP-10, and large amounts of IL-1β and TNF-α, but no IL-10 or IL-19. Interestingly, LPS-induced production of IL-10 and IL-19 was abolished in the presence of diABZI or MSA-2, whereas IL-1β and TNF-α were not inhibited. Surprisingly, we observed that tenfold lower (MSA-2, i.e. 2.5 μM) or 100-fold lower (diABZI, i.e. 1 nM) concentrations strongly stimulated secretion of anti-inflammatory IL-10 and IL-19, but little of IL-1β and TNF-α. Induction of IL-10 was associated with up-regulation of PRDM1 (Blimp-1). While cytokine secretion stimulated by the higher concentrations was accompanied by apoptosis as shown by cleavage of caspase-3 and PARP-1, the low concentrations did not trigger overt cell death yet induced cleavage of gasdermin-D. Our results reveal a previously unrecognized plasticity of human monocytes in their signal strength-dependent production of pro- versus anti-inflammatory cytokines upon STING activation.

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“…144 Alternative splicing Up to now, there are six alternative splicing isoforms of STING, reviewed elsewhere. 146 Interestingly, an isoform that lacks the transmembrane domain in its N-terminus was recently reported to locate on the plasma membrane, directly sensing the extracellular cGAMP and inducing IFN, 147 incidentally mirroring the first report of STING on the cell membrane in 2008. 10 However, how is the signal relayed to the nucleus remains enigmatic.…”

Section: The Regulation Of Sting Expression Genetic Control Of Sting ...mentioning

confidence: 92%

Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy

Zhang

Zhou

Ouyang

et al. 2022

Sig Transduct Target Ther

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

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An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP

Cited by 20 publications

References 31 publications

Regulation of cGAS/STING signaling and corresponding immune escape strategies of viruses

Regulation of cGAS/STING signaling and corresponding immune escape strategies of viruses

Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes

Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy

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