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miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans

Studying the evolutionary processes that shaped aging offers a path for understanding the causes of aging. The antagonistic pleiotropy theory for the evolution of aging proposes that the inverse correlation between age and natural selection strength allows positive selection of gene variants with ea...

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Autores principales: Ruediger, Cyrus, Karimzadegan, Siavash, Lin, Sonya, Shapira, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619845/
https://www.ncbi.nlm.nih.gov/pubmed/33755114
http://dx.doi.org/10.1093/genetics/iyab049
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author Ruediger, Cyrus
Karimzadegan, Siavash
Lin, Sonya
Shapira, Michael
author_facet Ruediger, Cyrus
Karimzadegan, Siavash
Lin, Sonya
Shapira, Michael
author_sort Ruediger, Cyrus
collection PubMed
description Studying the evolutionary processes that shaped aging offers a path for understanding the causes of aging. The antagonistic pleiotropy theory for the evolution of aging proposes that the inverse correlation between age and natural selection strength allows positive selection of gene variants with early-life beneficial contributions to fitness despite detrimental late-life consequences. However, mechanistic understanding of how this principle manifests in aging is still lacking. We previously identified antagonistic pleiotropy in the function of the Caenorhabditis elegans JNK homolog KGB-1, which provided stress protection in developing larvae, but sensitized adults to stress and shortened their lifespan. To a large extent, KGB-1’s contributions depended on age-dependent and opposing regulation of the stress-protective transcription factor DAF-16, but the underlying mechanisms remained unknown. Here, we describe a role for the microRNA miR-71 in mediating effects of KGB-1 on DAF-16 and downstream phenotypes. Fluorescent imaging along with genetic and survival analyses revealed age-dependent regulation of mir-71 expression by KGB-1—upregulation in larvae, but downregulation in adults—and showed that mir-71 was required both for late-life effects of KGB-1 (infection sensitivity and shortened lifespan), as well as for early life resistance to cadmium. While mir-71 disruption did not compromise development under protein-folding stress (known to depend on KGB-1), disruption of the argonaute gene alg-1, a central component of the microRNA machinery, did. These results suggest that microRNAs play a role in mediating age-dependent antagonistic contributions of KGB-1 to survival, with mir-71 playing a central role and additional microRNAs potentially contributing redundantly.
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spelling pubmed-86198452021-11-29 miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans Ruediger, Cyrus Karimzadegan, Siavash Lin, Sonya Shapira, Michael Genetics Investigation Studying the evolutionary processes that shaped aging offers a path for understanding the causes of aging. The antagonistic pleiotropy theory for the evolution of aging proposes that the inverse correlation between age and natural selection strength allows positive selection of gene variants with early-life beneficial contributions to fitness despite detrimental late-life consequences. However, mechanistic understanding of how this principle manifests in aging is still lacking. We previously identified antagonistic pleiotropy in the function of the Caenorhabditis elegans JNK homolog KGB-1, which provided stress protection in developing larvae, but sensitized adults to stress and shortened their lifespan. To a large extent, KGB-1’s contributions depended on age-dependent and opposing regulation of the stress-protective transcription factor DAF-16, but the underlying mechanisms remained unknown. Here, we describe a role for the microRNA miR-71 in mediating effects of KGB-1 on DAF-16 and downstream phenotypes. Fluorescent imaging along with genetic and survival analyses revealed age-dependent regulation of mir-71 expression by KGB-1—upregulation in larvae, but downregulation in adults—and showed that mir-71 was required both for late-life effects of KGB-1 (infection sensitivity and shortened lifespan), as well as for early life resistance to cadmium. While mir-71 disruption did not compromise development under protein-folding stress (known to depend on KGB-1), disruption of the argonaute gene alg-1, a central component of the microRNA machinery, did. These results suggest that microRNAs play a role in mediating age-dependent antagonistic contributions of KGB-1 to survival, with mir-71 playing a central role and additional microRNAs potentially contributing redundantly. Oxford University Press 2021-03-23 /pmc/articles/PMC8619845/ /pubmed/33755114 http://dx.doi.org/10.1093/genetics/iyab049 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Investigation
Ruediger, Cyrus
Karimzadegan, Siavash
Lin, Sonya
Shapira, Michael
miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans
title miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans
title_full miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans
title_fullStr miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans
title_full_unstemmed miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans
title_short miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans
title_sort mir-71 mediates age-dependent opposing contributions of the stress-activated kinase kgb-1 in caenorhabditis elegans
topic Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619845/
https://www.ncbi.nlm.nih.gov/pubmed/33755114
http://dx.doi.org/10.1093/genetics/iyab049
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