The STING1 network regulates autophagy and cell death

Zhang, Ruoxi; Kang, Rui; Tang, Daolin

doi:10.1038/s41392-021-00613-4

Cited by 147 publications

(102 citation statements)

References 201 publications

(200 reference statements)

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“…As unfettered pyroptosis can lead to myocardial tissue injury, targeting caspase-4-dependent pyroptosis may be a useful strategy for limiting IRI. Several studies have demonstrated that autophagy is a multifaceted modulator of cell death [ 28 , 29 ]. But, at present, we do not fully understand how autophagy regulation of pyroptosis protects CMECs against IRI.…”

Section: Discussionmentioning

confidence: 99%

Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury

Sun

Lu²,

Dong

et al. 2021

Cell Commun Signal

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Background Myocardial reperfusion injury is often accompanied by cell death and inflammatory reactions. Recently, pyroptosis is gradually recognized as pivotal role in cardiovascular disease. However, little is known about the regulatory role of beclin1 in the control of caspase-4 activation and pyroptosis. The present study confirmed whether beclin1 regulates caspase-4 mediated pyroptosis and thereby protects Human Cardiac microvascular endothelial cells (HCMECs) against injury. Methods TTC and Evan's blue dye, western blot, immunofluorescence and immunohistochemistry staining were performed in wild mice and transgenic mice with overexpression of beclin 1(BECN1-Tg). CMECs were transfected with a beclin1 lentivirus. The cell cytotoxicity was analyzed by LDH-Cytotoxicity Assay Kit. The protein levels of autophagy protein (Beclin1, p62 and LC3II/LC3I) and caspase-4/GSDMD pathway were determined by western blot. Autophagic vacuoles in cells were monitored with RFP-GFP-LC3 using fluorescence microscope. Results I/R caused caspase-4 activity and gasdermin D expression increase in vivo and in vitro. Overexpression of beclin1 in heart tissue and CMECs suppressed the caspase-4 activity and decreased the levels of gasdermin D; meanwhile beclin1 overexpression also reduced IL-1β levels, promoted autophagy (p62 expression was inhibited while LC3II expression was increased) in the heart and CMECs. Interestingly, beclin1 overexpression increased animal survival and attenuated myocardial infarct size (45 ± 6.13 vs 22 ± 4.37), no-reflow area (39 ± 5.22 vs 16 ± 2.54) post-myocardial ischemia reperfusion. Conclusions Induction of beclin-1 signaling can be a potential therapeutic target in myocardial reperfusion-induced microvascular injury.

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Section: Discussionmentioning

confidence: 99%

Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury

Sun

Lu²,

Dong

et al. 2021

Cell Commun Signal

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“…Canonical autophagy is depend on the ULK complex and TBK1, and is involved in the control of STING-mediated autophagy. Recently during replicative stress, cells were found to engage the STING-autophagy pathway to induce the autophagic cell death program, thereby inhibiting tumor growth [27,28]. Further study is necessary to reveal whether CX-5461 also has a role to induce the STING-autophagy pathway, and thereby regulate the outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Further, work needs to be done to elucidate the role of TP53 in response to CX-5461 and how the different mutations change the outcome. The inflammatory phenotype may be a STING-dependent activation, but it could also be partly associated with a senescence-associated secretory phenotype (SASP) as CX-5461 induces senescence in many cell types [28,29]. Most importantly, does the cancer specificity attributed to CX-5461 apply to this STING activation?…”

Section: Discussionmentioning

confidence: 99%

CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer

Cornelison

Biswas

Llaneza

et al. 2021

Cancers

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Epithelial ovarian cancer (EOC) is the deadliest of the gynecologic malignancies, with an overall survival rate of <30%. Recent research has suggested that targeting RNA polymerase I (POL I) with small-molecule inhibitors may be a viable therapeutic approach to combating EOC, even when chemoresistance is present. CX-5461 is one of the most promising POL I inhibitors currently being investigated, and previous reports have shown that CX-5461 treatment induces DNA damage response (DDR) through ATM/ATR kinase. Investigation into downstream effects of CX-5461 led us to uncovering a previously unreported phenotype. Treatment with CX-5461 induces a rapid accumulation of cytosolic DNA. This accumulation leads to transcriptional upregulation of ‘STimulator of Interferon Genes’ (STING) in the same time frame, phosphorylation of IRF3, and activation of type I interferon response both in vitro and in vivo. This activation is mediated and dependent on cyclic GMP–AMP synthase (cGAS). Here, we show THAT CX-5461 leads to an accumulation of cytosolic dsDNA and thereby activates the cGAS–STING–TBK1–IRF3 innate immune pathway, which induces type I IFN. CX-5461 treatment-mediated immune activation may be a powerful mechanism of action to exploit, leading to novel drug combinations with a chance of increasing immunotherapy efficacy, possibly with some cancer specificity limiting deleterious toxicities.

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“… 10 , 11 , 12 , 13 Subsequent studies revealed an immune-independent function of STING1 in promoting autophagy 14 and various kinds of cell death (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death) in various cells. 15 As a crucial part of the host immune defense, an aberrated activation of STING1 might induce an imbalance in the inflammation immune network. 16 Consequently, a hyperactivation of the STING1 signaling pathway plays an indispensable role in the development of various inflammatory diseases, such as Aicardi-Goutieres syndrome, COPA syndrome, and systemic lupus erythematosus.…”

Section: Introductionmentioning

confidence: 99%

STING1 in sepsis: Mechanisms, functions, and implications

Zhang

Kang

Tang

2022

Chinese Journal of Traumatology

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Sepsis is a life-threatening clinical syndrome and one of the most challenging health problems in the world. Pathologically, sepsis and septic shock are caused by a dysregulated host immune response to infection, which can eventually lead to multiple organ failure and even death. As an adaptor transporter between the endoplasmic reticulum and Golgi apparatus, stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173) has been found to play a vital role at the intersection of innate immunity, inflammation, autophagy, and cell death in response to invading microbial pathogens or endogenous host damage. There is ample evidence that impaired STING1, through its immune and non-immune functions, is involved in the pathological process of sepsis. In this review, we discuss the regulation and function of the STING1 pathway in sepsis and highlight it as a suitable drug target for the treatment of lethal infection.

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The STING1 network regulates autophagy and cell death

Cited by 147 publications

References 201 publications

Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury

Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury

CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer

STING1 in sepsis: Mechanisms, functions, and implications

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