STING directly activates autophagy to tune the innate immune response

Liu, Dong; Wu, Hao; Wang, Chenguang; Li, Yanjun; Tian, Huabin; Siraj, Sami; Sehgal, Sheikh Arslan; Wang, Xiaohui; Wang, Jun; Shang, Yue; Jiang, Zhengfan; Liu, Lei; Chen, Quan

doi:10.1038/s41418-018-0251-z

Cited by 295 publications

(272 citation statements)

References 44 publications

Supporting

Mentioning

260

Contrasting

Order By: Relevance

“…4d). In keeping with the previously established role of STING activation in augmenting autophagy 18,36,37 , we found that a majority of intracellular BCG-disA-OE bacilli were co-localized with LC3B in IFN-γ-activated primary BMDMs ( Fig. 4e-f), similar to our findings with urothelial cancer cells ( Fig.…”

Section: Macrophages Exposed To Sting Agonists Delivered By Intratumosupporting

confidence: 92%

“…S7a-b). In light of the fact that increased cytokine signaling from STING activation elicits increased autophagy 18,36,37 we evaluated the formation of LC3B puncta in human 5637 urothelial cancer cells exposed to BCG-disA-OE and BCG-WT. The majority of BCG-disA-OE bacilli co-localized with LC3B suggesting enhanced autophagic targeting by BCG-disA-OE, while similar co-localization was not observed with BCG-WT ( Fig.…”

Section: Bcg-disa-oe Is Also a Strong Inducer Of Pro-inflammatory Cytmentioning

confidence: 99%

See 1 more Smart Citation

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

View full text Add to dashboard Cite

BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood. We developed a recombinant BCG (rBCG) that releases the STING agonist, c-di-AMP. Compared with BCG, rBCG demonstrated superior antitumor efficacy in models of NMIBC, more potent pro-inflammatory cytokine responses, greater myeloid cell reprogramming (M1 shift) and enhanced epigenetic and metabolomic changes favoring antitumor immunity. These findings are signatures of trained immunity and reveal that STING pathway activation is a proximal trigger in trained immunity remodeling. Trained immunity may be a central mechanism for both BCG and rBCG antitumor activity in NMIBC. INTRODUCTION:Bacillus Calmette-Guérin (BCG)--the only FDA-approved bacterial agent for cancer immunotherapy--has been in use for the treatment of high-risk non-muscle invasive bladder cancer (NMIBC) as a first-line therapy since the late 1970s. More than one-third of patient's with NMIBC will experience tumor recurrence after receiving BCG, and these patients have limited options other than removal of the bladder and creation of a urinary diversion -a major life-altering event. Thus, there is a significant unmet need for improved versions of BCG that provide superior response rates and prevent disease progression 1 . At the current time intravesical options for bladder preserving therapy remain limited.Following bladder instillation, BCG induces a local inflammatory response accompanied by infiltration of granulocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and CD4 + and CD8 + T cells, accompanied by release of pro-inflammatory cytokines including IL-6, TNF-a, and IFN-g 2-7 . However, the specific immune mechanisms leading to BCG-mediated tumor eradication as well as BCG-resistance are not well-understood. BCG has been found to impart potent heterologous protection against non-related viral and bacterial infections; it elicits this protection via an innate immune memory mechanism known as trained immunity 8-11 . Trained immunity is characterized by metabolic, epigenetic and transcriptional reprogramming of both myeloid and lymphoid lineages 12-15 but it has not been extensively studied as an antitumor mechanism during BCG immunotherapy for NMIBC.Recent studies have implicated the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector, stimulator of interferon genes (STING), in a key immune response pathway known as the cytosolic surveillance pathway (CSP), which responds to DNA and cyclic dinucleotides aberrantly present in the cytosol [16][17][18][19] . Activated cGAS catalyzes the formation of 2′3′-cGAMP, a cyclic dinucleotide (CDN) that is a potent STING agonist.Activation of STING leads to stimulation of Type I interferon and NF-κB-mediated immune responses, including elevated dendritic cell priming and T-effector (Teff) cell recruitment 20-23 . 4Small molecule STING agonists elicit potent pro-inflammatory responses, and correspondingly have shown signific...

show abstract

Section: Macrophages Exposed To Sting Agonists Delivered By Intratumosupporting

confidence: 92%

Section: Bcg-disa-oe Is Also a Strong Inducer Of Pro-inflammatory Cytmentioning

confidence: 99%

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…After autophagy initiation, autophagy-related protein 9 (ATG9) undertakes the genesis of the autophagosome along with light chain3 (LC3) undergoing lipidation, thereby resulting in elongation of the autophagosome (88). LC3 can also be recruited directly by ERGIC-loading STING and bypass the classical autophagy pathway (68,89).…”

Section: Sting Downstream Signaling Promotes Ifnα/β Expression and Aumentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

View full text Add to dashboard Cite

Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

show abstract

“…In addition, the involvement of TBK1 during autophagy has been a matter of discussion. Some studies show that cells lacking TBK1 can still maintain autophagy-like events (LC3 conversion, puncta formation and autophagosomes formation) [16, 62] while other evidence suggests a critical role for TBK1 in phosphorylation of selective autophagy receptors and STING autophagosomal degradation [63, 64]. Importantly, our data in primary cells suggest that TBK1 is needed for STING-mediated autophagy…”

Section: Discussionmentioning

confidence: 57%

STING controls Herpes Simplex Virusin vivoindependent of type I interferon induction

Yamashiro

Wilson

Morrison

et al. 2019

Preprint

View full text Add to dashboard Cite

The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA derived from bacteria, viruses and tumors. To signal, the Cterminal tail (CTT) of STING recruits TBK1, a kinase that phosphorylates serine 365 (S365) in the CTT. Phospho-S365 acts as a docking site for IRF3, a transcription factor that is phosphorylated and activated by TBK1, leading to transcriptional induction of type I interferons (IFNs). IFNs are essential for antiviral immunity and are widely viewed as the primary output of STING signaling in mammals. However, other more evolutionarily ancestral responses, such as induction of NF-kB or autophagy, also occur downstream of STING. The relative importance of the various outputs of STING signaling during in vivo infections is unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) point mutation in STING exhibit normal susceptibility to Mycobacterium tuberculosis infection but, unexpectedly, are resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. Likewise, we find Irf3 -/mice exhibit resistance to HSV-1. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT or TBK1, suggesting that STING protects against HSV-1 upon TBK1 recruitment by the STING CTT, independent of IRF3 or type I IFNs. Interestingly, we find that STING-induced autophagy is a TBK1-dependent IRF3-independent process that is conserved in the STING S365A mice, and autophagy has previously been shown to be required for resistance to HSV-1. We thus propose that autophagy and perhaps other ancestral interferon-independent functions of STING are required for STING-dependent antiviral responses in vivo. Introduction 1 The immune response to pathogens is initiated upon detection of pathogen-2 associated molecular patterns (PAMPs) such as lipopolysaccharide, flagellin and nucleic 3 acids [1]. Double-stranded DNA (dsDNA) is an important PAMP for the detection of 4 many pathogens, including Mycobacterium tuberculosis and Herpes Simplex Virus-1 5 (HSV-1) [2-4]. In vertebrates, the intracellular presence of dsDNA is detected by cyclic-6 GMP-AMP Synthase (cGAS), a dsDNA-activated enzyme that produces a cyclic 7 dinucleotide (CDN) second messenger called 2′3′-cyclic-GMP-AMP (2′3′cGAMP) [5-8 10]. 2′3′cGAMP binds and activates the ER-resident transmembrane protein Stimulator 9 of Interferon Genes (STING). Transcriptional induction of type I IFNs is widely 10 presumed to be the primary output of STING signaling during antiviral defense. 11 However, STING is evolutionarily ancient, present even in bacteria [11] and in animals 12 such as the starlet sea anemone Nematostella vectensis and Drosophila melanogaster that 13 do not appear to encode type I interferons [12]. By contrast, autophagy and NF-κB 14 signaling are ancestral STING-induced signaling pathways, present in both N. vectensis 15 and D. melanogaster, raising the possibility that these pathways are the primary or 16 ancestral signaling outputs of STING [13-16]. 17 The ...

show abstract

STING directly activates autophagy to tune the innate immune response

Cited by 295 publications

References 44 publications

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

STING controls Herpes Simplex Virusin vivoindependent of type I interferon induction

Contact Info

Product

Resources

About