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Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation
Pathogen infection triggers host innate defenses which may result in the activation of regulated cell death (RCD) pathways such as apoptosis. Given a vital role in immunity, apoptotic effectors are often counteracted by pathogen-encoded antagonists. Mounting evidence indicates that programmed necros...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662602/ https://www.ncbi.nlm.nih.gov/pubmed/34436583 http://dx.doi.org/10.1093/molbev/msab256 |
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author | Palmer, Suzette N Chappidi, Sruthi Pinkham, Chelsea Hancks, Dustin C |
author_facet | Palmer, Suzette N Chappidi, Sruthi Pinkham, Chelsea Hancks, Dustin C |
author_sort | Palmer, Suzette N |
collection | PubMed |
description | Pathogen infection triggers host innate defenses which may result in the activation of regulated cell death (RCD) pathways such as apoptosis. Given a vital role in immunity, apoptotic effectors are often counteracted by pathogen-encoded antagonists. Mounting evidence indicates that programmed necrosis, which is mediated by the RIPK3/MLKL axis and termed necroptosis, evolved as a countermeasure to pathogen-mediated inhibition of apoptosis. Yet, it is unclear whether components of this emerging RCD pathway display signatures associated with pathogen conflict that are rare in combination but common to key host defense factors, namely, rapid evolution, viral homolog (virolog), and cytokine induction. We leveraged evolutionary sequence analysis that examines rates of amino acid replacement, which revealed: 1) strong and recurrent signatures of positive selection for primate and bat RIPK3 and MLKL, and 2) elevated rates of amino acid substitution on multiple RIPK3/MLKL surfaces suggestive of past antagonism with multiple, distinct pathogen-encoded inhibitors. Furthermore, our phylogenomics analysis across poxvirus genomes illuminated volatile patterns of evolution for a recently described MLKL viral homolog. Specifically, poxviral MLKLs have undergone numerous gene replacements mediated by duplication and deletion events. In addition, MLKL protein expression is stimulated by interferons in human and mouse cells. Thus, MLKL displays all three hallmarks of pivotal immune factors of which only a handful of factors like OAS1 exhibit. These data support the hypothesis that over evolutionary time MLKL functions—which may include execution of necroptosis—have served as a major determinant of infection outcomes despite gene loss in some host genomes. |
format | Online Article Text |
id | pubmed-8662602 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86626022021-12-10 Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation Palmer, Suzette N Chappidi, Sruthi Pinkham, Chelsea Hancks, Dustin C Mol Biol Evol Discoveries Pathogen infection triggers host innate defenses which may result in the activation of regulated cell death (RCD) pathways such as apoptosis. Given a vital role in immunity, apoptotic effectors are often counteracted by pathogen-encoded antagonists. Mounting evidence indicates that programmed necrosis, which is mediated by the RIPK3/MLKL axis and termed necroptosis, evolved as a countermeasure to pathogen-mediated inhibition of apoptosis. Yet, it is unclear whether components of this emerging RCD pathway display signatures associated with pathogen conflict that are rare in combination but common to key host defense factors, namely, rapid evolution, viral homolog (virolog), and cytokine induction. We leveraged evolutionary sequence analysis that examines rates of amino acid replacement, which revealed: 1) strong and recurrent signatures of positive selection for primate and bat RIPK3 and MLKL, and 2) elevated rates of amino acid substitution on multiple RIPK3/MLKL surfaces suggestive of past antagonism with multiple, distinct pathogen-encoded inhibitors. Furthermore, our phylogenomics analysis across poxvirus genomes illuminated volatile patterns of evolution for a recently described MLKL viral homolog. Specifically, poxviral MLKLs have undergone numerous gene replacements mediated by duplication and deletion events. In addition, MLKL protein expression is stimulated by interferons in human and mouse cells. Thus, MLKL displays all three hallmarks of pivotal immune factors of which only a handful of factors like OAS1 exhibit. These data support the hypothesis that over evolutionary time MLKL functions—which may include execution of necroptosis—have served as a major determinant of infection outcomes despite gene loss in some host genomes. Oxford University Press 2021-08-26 /pmc/articles/PMC8662602/ /pubmed/34436583 http://dx.doi.org/10.1093/molbev/msab256 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Discoveries Palmer, Suzette N Chappidi, Sruthi Pinkham, Chelsea Hancks, Dustin C Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation |
title | Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation |
title_full | Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation |
title_fullStr | Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation |
title_full_unstemmed | Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation |
title_short | Evolutionary Profile for (Host and Viral) MLKL Indicates Its Activities as a Battlefront for Extensive Counteradaptation |
title_sort | evolutionary profile for (host and viral) mlkl indicates its activities as a battlefront for extensive counteradaptation |
topic | Discoveries |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662602/ https://www.ncbi.nlm.nih.gov/pubmed/34436583 http://dx.doi.org/10.1093/molbev/msab256 |
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