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

Citation

Angosto-Bazarra, D and Alarcon-Vila, C and Hurtado-Navarro, L and Banos, M and Rivers-Auty, J and Pelegrin, P, Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality, BMC biology, 20, (9) pp. 1-18. ISSN 1741-7007 (2022) [Refereed Article]


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Copyright Statement

The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, (https://creativecommons.org/licenses/by/4.0/) 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.

DOI: doi:10.1186/s12915-021-01220-z

Abstract

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.

Conclusion: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.

Item Details

Item Type:Refereed Article
Keywords:Inflammation, evolution, gasdermin
Research Division:Biomedical and Clinical Sciences
Research Group:Immunology
Research Field:Cellular immunology
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Rivers-Auty, J (Dr Jack Auty)
ID Code:153517
Year Published:2022
Web of Science® Times Cited:4
Deposited By:Medicine
Deposited On:2022-09-21
Last Modified:2022-11-25
Downloads:3 View Download Statistics

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