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Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality

BACKGROUND: Gasdermins are ancient (>500million-years-ago) proteins, constituting a family of pore-forming proteins that allow the release of intracellular content including proinflammatory cytokines. Despite their importance in the immune response, and although gasdermin and gasdermin-like genes...

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Autores principales: Angosto-Bazarra, Diego, Alarcón-Vila, Cristina, Hurtado-Navarro, Laura, Baños, María C., Rivers-Auty, Jack, Pelegrín, Pablo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742441/
https://www.ncbi.nlm.nih.gov/pubmed/34996441
http://dx.doi.org/10.1186/s12915-021-01220-z
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author Angosto-Bazarra, Diego
Alarcón-Vila, Cristina
Hurtado-Navarro, Laura
Baños, María C.
Rivers-Auty, Jack
Pelegrín, Pablo
author_facet Angosto-Bazarra, Diego
Alarcón-Vila, Cristina
Hurtado-Navarro, Laura
Baños, María C.
Rivers-Auty, Jack
Pelegrín, Pablo
author_sort Angosto-Bazarra, Diego
collection PubMed
description BACKGROUND: Gasdermins are ancient (>500million-years-ago) proteins, constituting a family of pore-forming proteins that allow the release of intracellular content including proinflammatory cytokines. Despite their importance in the immune response, and although gasdermin and gasdermin-like genes have been identified across a wide range of animal and non-animal species, there is limited information about the evolutionary history of the gasdermin family, and their functional roles after infection. In this study, we assess the lytic functions of different gasdermins across Metazoa species, and use a mouse model of sepsis to evaluate the expression of the different gasdermins during infection. RESULTS: We show that the majority of gasdermin family members from distantly related animal clades are pore-forming, in line with the function of the ancestral proto-gasdermin and gasdermin-like proteins of Bacteria. We demonstrate the first expansion of this family occurred through a duplication of the ancestral gasdermin gene which formed gasdermin E and pejvakin prior to the divergence of cartilaginous fish and bony fish ~475 mya. We show that pejvakin from cartilaginous fish and mammals lost the pore-forming functionality and thus its role in cell lysis. We describe that the pore-forming gasdermin A formed ~320 mya as a duplication of gasdermin E prior to the divergence of the Sauropsida clade (the ancestral lineage of reptiles, turtles, and birds) and the Synapsid clade (the ancestral lineage of mammals). We then demonstrate that the gasdermin A gene duplicated to form the rest of the gasdermin family including gasdermins B, C, and D: pore-forming proteins that present a high variation of the exons in the linker sequence, which in turn allows for diverse activation pathways. Finally, we describe expression of murine gasdermin family members in different tissues in a mouse sepsis model, indicating function during infection response. CONCLUSIONS: In this study we explored the evolutionary history of the gasdermin proteins in animals and demonstrated that the pore-formation functionality has been conserved from the ancient proto-gasdermin protein. We also showed that one gasdermin family member, pejvakin, lost its pore-forming functionality, but that all gasdermin family members, including pejvakin, likely retained a role in inflammation and the physiological response to infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01220-z.
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spelling pubmed-87424412022-01-10 Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality Angosto-Bazarra, Diego Alarcón-Vila, Cristina Hurtado-Navarro, Laura Baños, María C. Rivers-Auty, Jack Pelegrín, Pablo BMC Biol Research Article BACKGROUND: Gasdermins are ancient (>500million-years-ago) proteins, constituting a family of pore-forming proteins that allow the release of intracellular content including proinflammatory cytokines. Despite their importance in the immune response, and although gasdermin and gasdermin-like genes have been identified across a wide range of animal and non-animal species, there is limited information about the evolutionary history of the gasdermin family, and their functional roles after infection. In this study, we assess the lytic functions of different gasdermins across Metazoa species, and use a mouse model of sepsis to evaluate the expression of the different gasdermins during infection. RESULTS: We show that the majority of gasdermin family members from distantly related animal clades are pore-forming, in line with the function of the ancestral proto-gasdermin and gasdermin-like proteins of Bacteria. We demonstrate the first expansion of this family occurred through a duplication of the ancestral gasdermin gene which formed gasdermin E and pejvakin prior to the divergence of cartilaginous fish and bony fish ~475 mya. We show that pejvakin from cartilaginous fish and mammals lost the pore-forming functionality and thus its role in cell lysis. We describe that the pore-forming gasdermin A formed ~320 mya as a duplication of gasdermin E prior to the divergence of the Sauropsida clade (the ancestral lineage of reptiles, turtles, and birds) and the Synapsid clade (the ancestral lineage of mammals). We then demonstrate that the gasdermin A gene duplicated to form the rest of the gasdermin family including gasdermins B, C, and D: pore-forming proteins that present a high variation of the exons in the linker sequence, which in turn allows for diverse activation pathways. Finally, we describe expression of murine gasdermin family members in different tissues in a mouse sepsis model, indicating function during infection response. CONCLUSIONS: In this study we explored the evolutionary history of the gasdermin proteins in animals and demonstrated that the pore-formation functionality has been conserved from the ancient proto-gasdermin protein. We also showed that one gasdermin family member, pejvakin, lost its pore-forming functionality, but that all gasdermin family members, including pejvakin, likely retained a role in inflammation and the physiological response to infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01220-z. BioMed Central 2022-01-07 /pmc/articles/PMC8742441/ /pubmed/34996441 http://dx.doi.org/10.1186/s12915-021-01220-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://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.
spellingShingle Research Article
Angosto-Bazarra, Diego
Alarcón-Vila, Cristina
Hurtado-Navarro, Laura
Baños, María C.
Rivers-Auty, Jack
Pelegrín, Pablo
Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
title Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
title_full Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
title_fullStr Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
title_full_unstemmed Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
title_short Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
title_sort evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742441/
https://www.ncbi.nlm.nih.gov/pubmed/34996441
http://dx.doi.org/10.1186/s12915-021-01220-z
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