TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization

Gao, Wenqing; Li, Yuanyuan; Liu, Xuehe; Wang, Sen; Mei, Pucheng; Chen, Zijun; Liu, Kewei; Li, Suhua; Xu, Xue-Wei; Gan, Jianhua; Wu, Jiaxue; Ji, Chaoneng; Chen, Ding; Liu, Xing; Lai, Yuping; He, Housheng Hansen; Lieberman, Judy; Wu, Hao; Chen, Xiangjun; Li, Jixi

doi:10.1038/s41418-021-00867-z

Cited by 40 publications

(26 citation statements)

References 49 publications

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“…Gao et al. identified TRIM21 as a new regulator of GSDMD-mediated pyroptosis ( 99 ). TRIM21 directly interacts with GSDMD through the PRY-SPRY domain in vivo and in vitro to maintain the stable expression of GSDMD in cell ( 99 ).…”

Section: Regulation Of Gsdmd Signaling In Pore Forming and Repairmentioning

confidence: 99%

“…identified TRIM21 as a new regulator of GSDMD-mediated pyroptosis ( 99 ). TRIM21 directly interacts with GSDMD through the PRY-SPRY domain in vivo and in vitro to maintain the stable expression of GSDMD in cell ( 99 ). The discovery of this regulatory factor also provides a new target for fine-tuning and treatment of inflammation-related diseases.…”

Section: Regulation Of Gsdmd Signaling In Pore Forming and Repairmentioning

confidence: 99%

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The Regulation and Modification of GSDMD Signaling in Diseases

Jiang

et al. 2022

Front. Immunol.

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Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and many other systemic diseases. Although canonical and non-canonical inflammasome-mediated classic GSDMD cleavage, GSDMD-NT migration to cell membrane, GSDMD-NT oligomerization, and pore forming have been well recognized, a few unique features of GSDMD in specific condition beyond its classic function, including non-lytic function of GSDMD, the modification and regulating mechanism of GSDMD signaling have also come to great attention and played a crucial role in biological processes and diseases. In the current review, we emphasized the GSDMD protein expression, stabilization, modification, activation, pore formation, and repair during pyroptosis, especially the regulation and modification of GSDMD signaling, such as GSDMD complex in polyubiquitination and non-pyroptosis release of IL-1β, ADP-riboxanation, NINJ1 in pore forming, GSDMD binding protein TRIM21, GSDMD succination, and Regulator-Rag-mTOR-ROS regulation of GSDMD. We also discussed the novel therapeutic strategies of targeting GSDMD and summarized recently identified inhibitors with great prospect.

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Section: Regulation Of Gsdmd Signaling In Pore Forming and Repairmentioning

confidence: 99%

Section: Regulation Of Gsdmd Signaling In Pore Forming and Repairmentioning

confidence: 99%

The Regulation and Modification of GSDMD Signaling in Diseases

Jiang

et al. 2022

Front. Immunol.

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“…Activated caspase-4, caspase-5, and caspase-11 specifically cleave the GSDMD, relieving intramolecular inhibition of the GSDMD N structural domain ( 108 ), and the GSDMD N terminus binds to cell membrane phospholipids, causing cell membrane pore formation, cell swelling, rupture, and induction of pyroptosis ( 108 ). The GSDMD N terminus also amplifies the inflammatory response by activating the NLRP3 inflammasome, which, in turn, activates caspase-1 ( 109 ), which stimulates the maturation of IL-18 and IL-1β precursors and secretes IL-18 and IL-1β extracellularly ( 110 ).…”

Section: Pyroptosismentioning

confidence: 99%

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Zhang

Liu

2022

Front. Immunol.

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Ovarian cancer (OC) is one of the most common malignancies that causes death in women and is a heterogeneous disease with complex molecular and genetic changes. Because of the relatively high recurrence rate of OC, it is crucial to understand the associated mechanisms of drug resistance and to discover potential target for rational targeted therapy. Cell death is a genetically determined process. Active and orderly cell death is prevalent during the development of living organisms and plays a critical role in regulating life homeostasis. Ferroptosis, a novel type of cell death discovered in recent years, is distinct from apoptosis and necrosis and is mainly caused by the imbalance between the production and degradation of intracellular lipid reactive oxygen species triggered by increased iron content. Necroptosis is a regulated non-cysteine protease–dependent programmed cell necrosis, morphologically exhibiting the same features as necrosis and occurring via a unique mechanism of programmed cell death different from the apoptotic signaling pathway. Pyroptosis is a form of programmed cell death that is characterized by the formation of membrane pores and subsequent cell lysis as well as release of pro-inflammatory cell contents mediated by the abscisin family. Studies have shown that ferroptosis, necroptosis, and pyroptosis are involved in the development and progression of a variety of diseases, including tumors. In this review, we summarized the recent advances in ferroptosis, necroptosis, and pyroptosis in the occurrence, development, and therapeutic potential of OC.

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“…Gao et al reported that TRIM21, a tripartite motif protein, binds to GSDMD via its PRY-SPRY domain, and positively regulates GSDMD-dependent pyroptosis. It maintains stable expression of GSDMD in resting cells, while inducing GSDMD-N aggregation during pyroptosis (Gao et al, 2022 ).…”

Section: Mechanisms Of Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Focus on the Role of the NLRP3 Inflammasome in Multiple Sclerosis: Pathogenesis, Diagnosis, and Therapeutics

Cui

et al. 2022

Front. Mol. Neurosci.

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Neuroinflammation is initiated with an aberrant innate immune response in the central nervous system (CNS) and is involved in many neurological diseases. Inflammasomes are intracellular multiprotein complexes that can be used as platforms to induce the maturation and secretion of proinflammatory cytokines and pyroptosis, thus playing a pivotal role in neuroinflammation. Among the inflammasomes, the nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome is well-characterized and contributes to many neurological diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. MS is a chronic autoimmune disease of the CNS, and its hallmarks include chronic inflammation, demyelination, and neurodegeneration. Studies have demonstrated a relationship between MS and the NLRP3 inflammasome. To date, the pathogenesis of MS is not fully understood, and clinical studies on novel therapies are still underway. Here, we review the activation mechanism of the NLRP3 inflammasome, its role in MS, and therapies targeting related molecules, which may be beneficial in MS.

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TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization

Cited by 40 publications

References 49 publications

The Regulation and Modification of GSDMD Signaling in Diseases

The Regulation and Modification of GSDMD Signaling in Diseases

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Focus on the Role of the NLRP3 Inflammasome in Multiple Sclerosis: Pathogenesis, Diagnosis, and Therapeutics

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