OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis

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Abstract

Background

Radioresistance is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure. Previous studies have focused on the deficits in cellular apoptosis as a mechanism for radioresistance; however, additional potential death modes involved in modulating radiosensitivity of NPC have not been explored.

Methods

Pyroptosis was assessed by phase-contrast imaging, LDH release assays, live cell imaging, and Western blotting. In vitro and in vivo assays were used to investigate the function of gasdermin E (GSDME) and ovarian tumor family deubiquitinase 4 (OTUD4). NPC tissues were analyzed using Western blotting, immunohistochemistry, and real-time PCR. The molecular mechanism was determined using immunoprecipitation assays and mass spectrometry.

Results

Live cell imaging revealed that 40—75% of irradiation-induced dead NPC cells were pyroptotic cells. Furthermore, irradiation-induced pyroptosis is triggered by GSDME, which are cleaved by activated caspase-3 in the intrinsic mitochondrial pathway. Additionally, GSDME was significantly downregulated in radioresistant NPC specimens. Low GSDME expression was a predictor of worse prognosis and conferred NPC radioresistance both in vitro and in vivo. Mechanistically, OTUD4 deubiquitinated and stabilized GSDME, enhancing radiosensitivity of NPC cells by promoting pyroptosis. Clinically, OTUD4 was significantly correlated with GSDME in NPC biopsies, and patients with low expression of both OTUD4 and GSDME suffered the worst radiotherapy response and survival.

Conclusions

GSDME-dependent pyroptosis is a critical determinant of radiosensitivity in NPC, and is modulated by OTUD4 via deubiquitinating and stabilizing GSDME. These findings reveal a promising novel direction to investigate radioresistance and suggest potential therapeutic targets for sensitizing NPC to radiotherapy.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-022-02533-9.

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Most cited references 42

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Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

Jianjin Shi, Yue Zhao, Kun Wang … (2015)

Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.

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Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a Gasdermin

Yupeng Wang, Wenqing Gao, Xuyan Shi … (2017)

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Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.

Nobuhiko Kayagaki, Irma B Stowe, Bettina Lee … (2015)

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.

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Author and article information

Contributors

Lin Wang: wangl1@sysucc.org.cn3

Jianchuan Xia: xiajch@mail.sysu.edu.cn

Chong Zhao: zhaoch@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 21 November 2022

Publication date PMC-release: 21 November 2022

Publication date Collection: 2022

Volume: 41

Electronic Location Identifier: 328

Affiliations

[1 ]GRID grid.488530.2, ISNI 0000 0004 1803 6191, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, ; Guangzhou, 510060 China

[2 ]GRID grid.488530.2, ISNI 0000 0004 1803 6191, Department of Nasopharyngeal Carcinoma, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, , Sun Yat-Sen University Cancer Center, ; Guangzhou, 510060 China

[3 ]GRID grid.488530.2, ISNI 0000 0004 1803 6191, Department of Biotherapy, , Sun Yat-Sen University Cancer Center, ; Guangzhou, 510060 China

[4 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Department of Urology, , Peking University Third Hospital, ; Beijing, 100000 China

[5 ]GRID grid.412793.a, ISNI 0000 0004 1799 5032, Division of Gastroenterology, , Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430030 China

Article

Publisher ID: 2533

DOI: 10.1186/s13046-022-02533-9

PMC ID: 9677691

PubMed ID: 36411454

SO-VID: 9dd024c3-288a-420e-be08-6e042e0cd9d7

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 11 August 2022

Date accepted : 6 November 2022

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: otud4,gsdme,pyroptosis,radioresistance,nasopharyngeal carcinoma

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: otud4, gsdme, pyroptosis, radioresistance, nasopharyngeal carcinoma

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OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Karger: Oncology

Most cited references 42

Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a Gasdermin

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.

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Cited by 13

Most referenced authors 915