Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions

Hansen, Justin M.; Jong, Maarten F. de; Wu, Qi; Zhang, Li-Shu; Heisler, David B.; Alto, Laura Taylor; Alto, Neal M.

doi:10.1016/j.cell.2021.04.036

Cited by 118 publications

(164 citation statements)

References 76 publications

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“…In addition, HUWE1 stimulates inflammasomes activation by promoting K27-linked polyubiquitination of NLRP3, AIM2, and NLRC4, which strengthen host defense against bacterial infection [ 29 ]. Gasdermin B (GSDMB), another member of the gasdermin family, has also been recently found to participate in ubiquitination-mediated pyroptosis that blocks bactericidal functions of NK cells [ 30 ]. Given that pyroptosis regulation is important in the signaling of cell death, GSDMD ubiquitination may broadly be thought to regulate the function of GSDMD and the activities of different inflammasomes [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

Shi

Yang

et al. 2022

Cell Death Dis

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Gasdermin D (GSDMD) participates in the activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.

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Section: Introductionmentioning

confidence: 99%

E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

Shi

Yang

et al. 2022

Cell Death Dis

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“…To test if phosphatidylserine can indeed inhibit the lytic ability of perforin, we produced liposomes composed of phosphatidylcholine and varying molar concentrations (0, 30, 60, and 100%) of phosphatidylserine and containing 5,6-carboxyfluorescein. The 5,6-carboxyfluorescein release can be recorded as a measure of liposome lysis ( 40 ). Perforin lytic ability was found to be significantly reduced against liposomes composed of 60% and 100% phosphatidylserine ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The protocol for liposome preparation and dye release assay was adapted from Hansen et al. ( 40 ). Briefly, 1,2-dioleoyl-sn-glycero-3-phosphocholine (Avanti Polar Lipids) and Brain L-α-phosphatidylserine (Avanti Polar Lipids) were dissolved in chloroform and mixed at varying molar concentrations.…”

Section: Methodsmentioning

confidence: 99%

Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity

Tuomela

Mukherjee

Ambrose

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The impact of radiotherapy on the interaction between immune cells and cancer cells is important not least because radiotherapy can be used alongside immunotherapy as a cancer treatment. Unexpectedly, we found that X-ray irradiation of cancer cells induced significant resistance to natural killer (NK) cell killing. This was true across a wide variety of cancer-cell types as well as for antibody-dependent cellular cytotoxicity. Resistance appeared 72 h postirradiation and persisted for 2 wk. Resistance could also occur independently of radiotherapy through pharmacologically induced cell-cycle arrest. Crucially, multiple steps in NK-cell engagement, synapse assembly, and activation were unaffected by target cell irradiation. Instead, radiotherapy caused profound resistance to perforin-induced calcium flux and lysis. Resistance also occurred to a structurally similar bacterial toxin, streptolysin O. Radiotherapy did not affect the binding of pore-forming proteins at the cell surface or membrane repair. Rather, irradiation instigated a defect in functional pore formation, consistent with phosphatidylserine-mediated perforin inhibition. In vivo, radiotherapy also led to a significant reduction in NK cell–mediated clearance of cancer cells. Radiotherapy-induced resistance to perforin also constrained chimeric antigen receptor T-cell cytotoxicity. Together, these data establish a treatment-induced resistance to lymphocyte cytotoxicity that is important to consider in the design of radiotherapy–immunotherapy protocols.

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“…flexneri . 161 This study suggests that post‐translational modification, such as ubiquitination, might serve as an important way to enhance or antagonize pyroptosis. It will be very attractive to figure out the potential regulatory effects of other post‐translational modifications on pyroptosis in the future.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 86%

Pyroptosis: A promising therapeutic target for noninfectious diseases

Zheng

et al. 2021

Cell Proliferation

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Pyroptosis, which is characterized by gasdermin family protein‐mediated pore formation, cellular lysis and the release of pro‐inflammatory cytokines, is a form of programmed cell death associated with intracellular pathogens‐induced infection. However, emerging evidence indicates that pyroptosis also contributes to sterile inflammation. In this review, we will first illustrate the biological process of pyroptosis. Then, we will focus on the pathogenic effects of pyroptosis on multiple noninfectious disorders. At last, we will characterize several specific pyroptotic inhibitors targeting the pyroptotic signalling pathway. These data demonstrate that pyroptosis plays a prominent role in sterile diseases, thereby providing a promising approach to the treatment of noninfective inflammatory disorders.

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Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions

Cited by 118 publications

References 76 publications

E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity

Pyroptosis: A promising therapeutic target for noninfectious diseases

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