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      IP3R1 regulates Ca 2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury

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          Abstract

          Intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca 2+ from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial enzymes, infarct area, Ca 2+ level, NLRP3/Caspase-1, and pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block Ca 2+ channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced Ca 2+ overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca 2+ overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca 2+ level caused H/R-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits Ca 2+ overload, thus alleviating pyroptosis and MI/R injury.

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          Inflammasomes: mechanism of assembly, regulation and signalling.

          Petr Broz, Vishva Dixit (2016)
          Inflammasomes are multiprotein signalling platforms that control the inflammatory response and coordinate antimicrobial host defences. They are assembled by pattern-recognition receptors following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells, and they activate inflammatory caspases to produce cytokines and to induce pyroptotic cell death. The clinical importance of inflammasomes reaches beyond infectious disease, as dysregulated inflammasome activity is associated with numerous hereditary and acquired inflammatory disorders. In this Review, we discuss the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammasome assembly, signalling and regulation.
          Article 0 comments Cited 1045 times – based on 0 reviews     Review now
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            Pore-forming activity and structural autoinhibition of the gasdermin family.

            Jingjin Ding, Kun Wang, Wang-Wang Liu … (2016)
            Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and artificially transformed bacteria. Gasdermin-N moved to the plasma membrane during pyroptosis. Purified gasdermin-N efficiently lysed phosphoinositide/cardiolipin-containing liposomes and formed pores on membranes made of artificial or natural phospholipid mixtures. Most gasdermin pores had an inner diameter of 10–14 nm and contained 16 symmetric protomers. The crystal structure of GSDMA3 showed an autoinhibited two-domain architecture that is conserved in the gasdermin family. Structure-guided mutagenesis demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.
            Article 0 comments Cited 906 times – based on 0 reviews     Review now
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              Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion

              Wan-ting He, Haoqiang Wan, Lichen Hu … (2015)
              Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd −/− cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd −/− cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.
              Article 0 comments Cited 815 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Liangqing Zhang:
                ORCID: http://orcid.org/0000-0002-4450-656X
                Zhanglianq0116@163.com
                Yijun Liu: seukke235tb791@163.com
                Journal
                Journal ID (nlm-ta): Cell Death Discov
                Journal ID (iso-abbrev): Cell Death Discov
                Title: Cell Death Discovery
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2058-7716
                Publication date (Electronic): 10 February 2021
                Publication date PMC-release: 10 February 2021
                Publication date Collection: 2021
                Volume: 7
                Electronic Location Identifier: 31
                Affiliations
                GRID grid.410560.6, ISNI 0000 0004 1760 3078, Department of Anesthesiology, , Affiliated Hospital of Guangdong Medical university, ; Zhanjiang, Guangdong P.R. China
                Author information
                http://orcid.org/0000-0002-4450-656X
                Article
                Publisher ID: 404
                DOI: 10.1038/s41420-021-00404-4
                PMC ID: 7876122
                PubMed ID: 33568649
                SO-VID: 0e39c950-144c-4164-8bfa-c85984fd9a4f
                Copyright © © The Author(s) 2021
                License:

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 31 July 2020
                Date revision received : 10 November 2020
                Date accepted : 24 November 2020
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                Keywords: calcium channels,thromboembolism
                Data availability:
                Keywords: calcium channels, thromboembolism

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