Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells

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  • dc.contributor.author Oltra Sanchis, Sara
  • dc.contributor.author Albanell Mestres, Joan
  • dc.contributor.author Moreno-Bueno, Gema
  • dc.date.accessioned 2024-02-13T09:20:47Z
  • dc.date.available 2024-02-13T09:20:47Z
  • dc.date.issued 2023
  • dc.description.abstract Gasdermin (GSDM)-mediated pyroptosis is functionally involved in multiple diseases, but Gasdermin-B (GSDMB) exhibit cell death-dependent and independent activities in several pathologies including cancer. When the GSDMB pore-forming N-terminal domain is released by Granzyme-A cleavage, it provokes cancer cell death, but uncleaved GSDMB promotes multiple pro-tumoral effects (invasion, metastasis, and drug resistance). To uncover the mechanisms of GSDMB pyroptosis, here we determined the GSDMB regions essential for cell death and described for the first time a differential role of the four translated GSDMB isoforms (GSDMB1-4, that differ in the alternative usage of exons 6-7) in this process. Accordingly, we here prove that exon 6 translation is essential for GSDMB mediated pyroptosis, and therefore, GSDMB isoforms lacking this exon (GSDMB1-2) cannot provoke cancer cell death. Consistently, in breast carcinomas the expression of GSDMB2, and not exon 6-containing variants (GSDMB3-4), associates with unfavourable clinical-pathological parameters. Mechanistically, we show that GSDMB N-terminal constructs containing exon-6 provoke cell membrane lysis and a concomitant mitochondrial damage. Moreover, we have identified specific residues within exon 6 and other regions of the N-terminal domain that are important for GSDMB-triggered cell death as well as for mitochondrial impairment. Additionally, we demonstrated that GSDMB cleavage by specific proteases (Granzyme-A, Neutrophil Elastase and caspases) have different effects on pyroptosis regulation. Thus, immunocyte-derived Granzyme-A can cleave all GSDMB isoforms, but in only those containing exon 6, this processing results in pyroptosis induction. By contrast, the cleavage of GSDMB isoforms by Neutrophil Elastase or caspases produces short N-terminal fragments with no cytotoxic activity, thus suggesting that these proteases act as inhibitory mechanisms of pyroptosis. Summarizing, our results have important implications for understanding the complex roles of GSDMB isoforms in cancer or other pathologies and for the future design of GSDMB-targeted therapies.
  • dc.description.sponsorship This study has been supported by the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (MICINN-AEI, PID2019-104644RB-I00, PDC2022-133252-I00) -GMB-, (PID2021-126625OB-I00-MCIN/AEI/10.13039/501100011033 FEDER, EU.2022- and DTS20-00024 -ISCIII-) -PGP-, the Instituto de Salud Carlos III (CIBERONC, CB16/12/00295 -GMB- and CB16/12/00241 -JA-, and AC21_2/00020 ERA PerMed ERA-NET, PMP22/00054 Immune4ALL Personalized Medicine -GMB-, cofunded by NextGenerationEU), I “Semilla” CIBERONC-GEICAM Grant -GMB- and the AECC Scientific Foundation (FCAECC PROYE19036MOR and GCTRA18014MATI -GMB-), the National Institutes of Health (NIH, USA) (R01-DK123475) -J-KK- and it has been also supported by a startup fund to -J-KK- from the Ohio State University, the College of Medicine, Department of Surgery. DS contract is funded by CIBERONC partly supported by FEDER funds. SO is funded by the FCAECC (POSTD20028OLTR), SC is funded by the MICINN-AEI PRE2020-095658.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Oltra SS, Colomo S, Sin L, Pérez-López M, Lázaro S, Molina-Crespo A et al. Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells. Cell Death Differ. 2023 May;30(5):1366-81. DOI: 10.1038/s41418-023-01143-y
  • dc.identifier.doi http://dx.doi.org/10.1038/s41418-023-01143-y
  • dc.identifier.issn 1350-9047
  • dc.identifier.uri http://hdl.handle.net/10230/59092
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Cell Death Differ. 2023 May;30(5):1366-81
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104644RB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-126625OB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PDC2022-133252-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PRE2020-095658
  • dc.rights © 2023, The Author(s). 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/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer
  • dc.subject.keyword Tumour biomarkers
  • dc.title Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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