Redox homeostasis maintained by GPX4 facilitates STING activation

Jia, Mutian; Qin, Danhui; Zhao, Chenyang; Chai, Li; Yu, Zhongxia; Wang, Wenwen; Li, Tong; Lv, Lin; Wang, Yuanyuan; Rehwinkel, Jan; Yu, Jinming; Zhao, Wei

doi:10.1038/s41590-020-0699-0

Cited by 265 publications

(212 citation statements)

References 56 publications

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“…Consistent with our data that STING undergoes redox modification, a recent study demonstrates that glutathione peroxidase 4 (GPX4), an enzyme that protects cells against membrane lipid peroxidation and maintains redox homeostasis, is required for the activation of the cGAS-STING pathway. This report also shows that GPX4 is required for innate immune responses against herpes simplex virus 1 ( Jia et al, 2020 ). These data, along with our data, support a model whereby ROS promote DNA virus acute replication in a STING-dependent manner.…”

Section: Discussionmentioning

confidence: 59%

Reactive oxygen species oxidize STING and suppress interferon production

Tao

Lemoff

Zarek

et al. 2020

eLife

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Reactive oxygen species (ROS) are by-products of cellular respiration that can promote oxidative stress and damage cellular proteins and lipids. One canonical role of ROS is to defend the cell against invading bacterial and viral pathogens. Curiously, some viruses, including herpesviruses, thrive despite the induction of ROS, suggesting that ROS are beneficial for the virus. However, the underlying mechanisms remain unclear. Here, we found that ROS impaired interferon response during murine herpesvirus infection and that the inhibition occurred downstream of cytoplasmic DNA sensing. We further demonstrated that ROS suppressed the type I interferon response by oxidizing Cysteine 147 on murine stimulator of interferon genes (STING), an ER-associated protein that mediates interferon response after cytoplasmic DNA sensing. This inhibited STING polymerization and activation of downstream signaling events. These data indicate that redox regulation of Cysteine 147 of mouse STING, which is equivalent to Cysteine 148 of human STING, controls interferon production. Together, our findings reveal that ROS orchestrates anti-viral immune responses, which can be exploited by viruses to evade cellular defenses.

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Section: Discussionmentioning

confidence: 59%

Reactive oxygen species oxidize STING and suppress interferon production

Tao

Lemoff

Zarek

et al. 2020

eLife

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“…Human embryonic kidney (HEK293T) cells were obtained from the American Type Culture Collection (Manassas, VA). Mouse embryonic fibroblasts (MEFs) were generated from female pregnant for 13-14 days mice 43 . In short, pregnant females were sacrificed by cervical dislocation, embryos were taken out, and the fetal viscera, head and limbs were excised.…”

Section: Methodsmentioning

confidence: 99%

“…For re-IP, after the first IP, the beads were denatured by boiling in IP buffer containing 1% SDS. The eluates were diluted with IP buffer, and IP was performed similar to the first IP 43 . For immunoblot analysis, cells were lysed with M-PER Protein Extraction Reagent (Pierce, Rockford, IL, cat.…”

Section: Methodsmentioning

confidence: 99%

“…Assay of luciferase activity. Luciferase activity was measured using the Dual-Luciferase Reporter Assay system according to the manufacturer's instructions (Promega) 36,43 . In short, HEK293T cells were cotransfected with the mixture of the indicated luciferase reporter plasmid, pRL-TK-Renilla-luciferase plasmid, and the indicated expression plasmids using Jet-PEI transfection reagent (Polyplus, cat.…”

Section: Methodsmentioning

confidence: 99%

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UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression

Song

Zhao

et al. 2020

Nat Commun

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NOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. Deubiquitination of NLRP3 is considered a key step in NLRP3 inflammasome activation. However, the mechanisms by which deubiquitination controls NLRP3 inflammasome activation are unclear. Here, we show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. In addition, the UAF1/USP12 and UAF1/USP46 complexes promote NF-κB activation, enhance the transcription of NLRP3 and proinflammatory cytokines (including pro-IL-1β, TNF, and IL-6) by inhibiting ubiquitination-mediated degradation of p65. Consequently, Uaf1 deficiency attenuates NLRP3 inflammasome activation and IL-1β secretion both in vitro and in vivo. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation.

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“…Treatment of nitro-fatty acids could modifies Cys88 and Cys91 of STING through nitroalkylation in ER, inhibiting normal palmitoylation [38]. Additionally, STING was recently showed to be carbonylated by lipid peroxidation, and STING carbonylation inhibited STING palmitoylation and subsequent activation [39]. Sumoylation plays an important role in protein stability.…”

Section: Regulation and Modification Of Sting Signalingmentioning

confidence: 99%

Cytosolic sensor STING in mucosal immunity: a master regulator of gut inflammation and carcinogenesis

Zhou

Xia

et al. 2021

J Exp Clin Cancer Res

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The stimulator of interferon genes (STING) connects microbial cytosolic sensing with host cell effector functions. STING signaling plays a central role in cyclic dinucleotides (CDNs) and DNA sensing to induce secretion of interferons and pro-inflammatory mediators. Although activated STING signaling favors antimicrobial progress and facilitates mucosal would healing, its role in mucosal immunity and gut homeostasis is paradoxical, ranging from positive and negative effects within the gut. In our review, we summarize recent advance of STING signaling in gut homeostasis and inflammation, especially focusing on its molecular basis in mucosal immune response. Deep understanding of the regulatory mechanisms of intestinal STING pathway could promote clinical manipulation of this fundamental signaling as a promising immunomodulatory therapy.

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Redox homeostasis maintained by GPX4 facilitates STING activation

Cited by 265 publications

References 56 publications

Reactive oxygen species oxidize STING and suppress interferon production

Reactive oxygen species oxidize STING and suppress interferon production

UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression

Cytosolic sensor STING in mucosal immunity: a master regulator of gut inflammation and carcinogenesis

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