miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans.
miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans.
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miR-71介导秀丽隐杆线虫中应激激活激酶KGB-1的年龄依赖性相反贡献
DOI：
10.1093/genetics/iyab049
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发表时间：
2021-06-24
期刊：
影响因子：
3.3
通讯作者：
Shapira M
中科院分区：
文献类型：
--
作者：
Ruediger C;Karimzadegan S;Lin S;Shapira M
研究形成衰老的进化过程为理解衰老的原因提供了一条途径。衰老进化的拮抗多效性理论提出，年龄和自然选择强度之间的负相关性允许对基因变体进行正向选择，这些基因变体对早期生命的健康有益，尽管对晚期生命有害。然而，对这一原则如何在衰老中表现的机械理解仍然缺乏。我们先前确定了秀丽隐杆线虫JNK同源物KGB-1的功能中的拮抗多效性，其在发育中的幼虫中提供应激保护，但使成虫对应激敏感并缩短其寿命。在很大程度上，KGB-1的贡献取决于年龄依赖性和应激保护转录因子β-16的反向调节，但其潜在机制仍不清楚。在这里，我们描述了microRNA miR-71在介导KGB-1对miR-16和下游表型的影响中的作用。荧光成像沿着遗传和存活分析揭示了KGB-1对mir-71表达的年龄依赖性调节--在幼虫中上调，但在成虫中下调--并表明mir-71对KGB-1的晚期效应（感染敏感性和寿命缩短）以及早期对镉的抗性都是必需的。虽然mir-71的破坏不会影响蛋白质折叠应激（已知依赖于KGB-1）下的发育，但argonaute基因alg-1（microRNA机制的核心组成部分）的破坏会影响发育。这些结果表明，microRNA在介导KGB-1对生存的年龄依赖性拮抗作用中发挥作用，其中mir-71发挥核心作用，其他microRNA可能发挥冗余作用。
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.
使用现有的和诱导的非整倍性化的二倍体非舒张生物的单倍型映射。
影响因子：
4.5
作者：
Legrand, Melanie;Forche, Anja;Selmecki, Anna;Chan, Christine;Kirkpatrick, David T.;Berman, Judith
通讯作者：
Berman, Judith