STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection

Wang, Wenbiao; Hu, Dingwen; Wu, Chao; Feng, Yuqian; Li, Aixin; Liu, Weiyong; Wang, Yingchong; Chen, Keli; Tian, Mingfu; Xiao, Feng; Zhang, Qi; Shereen, Muhammad Adnan; Chen, Weijie; Pan, Pan; Wan, Pin; Wu, Kailang; Wu, Jianguo

doi:10.1371/journal.ppat.1008335

Cited by 141 publications

(114 citation statements)

References 50 publications

(68 reference statements)

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“…Among others, Song et al used transfected HEK293T cells to demonstrate that NLRP3 phosphorylation mediated by JNK1 is an essential priming event for inflammasome activation [ 22 ]. Wang et al recently utilized HEK293T cells to prove that the stimulator of interferon genes (STING) binds to NLRP3 thus mediating its localization into the ER and determining its de-ubiquitination required for inflammasome activation [ 102 ]. Finally, Mao et al used HEK293T cells to demonstrate that Bruton tyrosine kinase (BTK) binds to NLRP3 to regulate its activation, therefore suggesting that BTK deficiency is associated with several inflammatory NLRP3-mediated diseases [ 103 ].…”

Section: Cell Models To Study Nlrp3 Inflammasome Biologymentioning

confidence: 99%

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Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Zito

Buscetta

Cimino

et al. 2020

IJMS

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The NLRP3 inflammasome is a multi-protein complex that initiates innate immunity responses when exposed to a wide range of stimuli, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Inflammasome activation leads to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and to pyroptotic cell death. Over-activation of NLRP3 inflammasome has been associated with several chronic inflammatory diseases. A deep knowledge of NLRP3 inflammasome biology is required to better exploit its potential as therapeutic target and for the development of new selective drugs. To this purpose, in the past few years, several tools have been developed for the biological characterization of the multimeric inflammasome complex, the identification of the upstream signaling cascade leading to inflammasome activation, and the downstream effects triggered by NLRP3 activation. In this review, we will report cellular models and cellular, biochemical, and biophysical assays that are currently available for studying inflammasome biology. A special focus will be on those models/assays that have been used to identify NLRP3 inhibitors and their mechanism of action.

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Section: Cell Models To Study Nlrp3 Inflammasome Biologymentioning

confidence: 99%

“…Immunofluorescence can be used to study protein expression and localization. For example, it has been reported that NLRP3 localization on mitochondria membranes under certain circumstances is required for optimal inflammasome activation [ 91 , 102 , 126 ].…”

Section: Cellular Biochemical and Biophysical Assays To Evaluatementioning

confidence: 99%

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Zito

Buscetta

Cimino

et al. 2020

IJMS

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show abstract

“…Herpes virus, including HHV-6 and -7 have been more frequently reported as triggers of KD [28], and, interestingly, they also activate the STING pathway. Upon HSV infection and cytosolic DNA stimulation, STING binds to NLRP3 and promotes the inflammasome activation and IL-1β release, a cytokine critically required in mouse models of KD [29].…”

Section: Introductionmentioning

confidence: 99%

Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

Berthelot

Drouet

Lioté

2020

Emerging Microbes & Infections

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We previously made the hypothesis that STING contributes to COVID-19. The present review detail new arguments for over-activation of STING pathways in COVID-19, following the description of hyper-coagulability and Kawasaki-like diseases in children. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guérin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Over-activation of the STING-pathway promotes hyper-coagulability through release of interferon-β and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients. Triggering of the STING pathway by alien or self cytosolic DNA, can activate (from right to left): IRF-3 (partly inhibited by IVIgs after linking of FcγRIIa [38]), NK-κB, and the inflammasome NLRP3 [9]. This might occur even more frequently in COVID-19 patients with simultaneous enhancement of STING synthesis following excess of angiotensin II on cell membrane, secondary to the ACE1/2 imbalance (more pronounced in males), induced by the binding of SARS-CoV2 to ACE2 [42-45].

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“…Upon subsequent activation signals, BRCC3 removes K63‐linked ubiquitin from NLRP3, allowing inflammasome activation 37 . In addition, the stimulator of IFN genes (STING) has been shown, upon Herpes simplex virus type 1 (HSV‐1) infection and cytosolic DNA stimulation, to bind to NLRP3 and localize it to the endoplasmic reticulum, where it then removes K48‐ and K63‐linked polyubiquitination of NLRP3, facilitating inflammasome activation 38 . Additional DUBs, such as ubiquitin‐specific peptidase 7 (USP7) and USP47, have also been shown to play an essential role in regulating inflammasome activation, although they are activated primarily in response to NLRP3 activation signals like nigericin and calcium pyrophosphate dihydrate (CPPD) crystals 39 …”

Section: Ubiquitination Of Nlrp3mentioning

confidence: 99%

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

McKee

Coll

2020

Journal of Leukocyte Biology

139

138

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The NLRP3 (NOD‐, LRR‐, and pyrin domain‐containing protein 3) inflammasome is an immunological sensor that detects a wide range of microbial‐ and host‐derived signals. Inflammasome activation results in the release of the potent pro‐inflammatory cytokines IL‐1β and IL‐18 and triggers a form of inflammatory cell death known as pyroptosis. Excessive NLRP3 activity is associated with the pathogenesis of a wide range of inflammatory diseases, thus NLRP3 activation mechanisms are an area of intensive research. NLRP3 inflammasome activation is a tightly regulated process that requires both priming and activation signals. In particular, recent research has highlighted the highly complex nature of the priming step, which involves transcriptional and posttranslational mechanisms, and numerous protein binding partners. This review will describe the current understanding of NLRP3 priming and will discuss the potential opportunities for targeting this process therapeutically to treat NLRP3‐associated diseases.

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STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection

Cited by 141 publications

References 50 publications

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

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