年龄依赖性热休克激素对 HSF-1 缺乏的影响表明,年轻的秀丽隐杆线虫体内存在一种由未折叠蛋白反应和先天性免疫介导的补偿机制。

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-06-19 DOI:10.1111/acel.14246
Dániel Kovács, János Barnabás Biró, Saqib Ahmed, Márton Kovács, Tímea Sigmond, Bernadette Hotzi, Máté Varga, Viktor Vázsony Vincze, Umar Mohammad, Tibor Vellai, János Barna
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引用次数: 0

摘要

转录因子 HSF-1(热休克因子 1)是真核细胞热休克反应的主调节因子,可维持细胞的蛋白稳态。该蛋白在防止细胞老化和神经变性方面起着保护作用,同时还能介导肿瘤发生。因此,调节 HSF-1 在人体中的活性有望治疗这些病症。HSF-1 功能的丧失通常与应激耐受性受损有关。与这一传统认知相反,我们在这里展示了线虫HSF-1的失活会导致幼成体阶段的耐热性增强,而与野生型相比,幼成体阶段的动物缺乏HSF-1确实会导致耐热性下降。此外,基因表达分析证实,在幼年期,HSF-1 缺乏会诱导不同的细胞应激反应和免疫相关信号通路。我们还证明,缺失 HSF-1 的幼虫对蛋白毒性应激的耐受性增强需要内质网未折叠蛋白反应和 SKN-1/Nrf2 介导的氧化应激反应途径以及先天免疫相关途径的活性,这表明 HSF-1 与这些保守的应激反应系统之间存在相互补偿的相互作用。类似的补偿性分子网络也可能在更高的动物类群中运行,因此在人类体内操纵 HSF-1 的活性可能会产生意想不到的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Age-dependent heat shock hormesis to HSF-1 deficiency suggests a compensatory mechanism mediated by the unfolded protein response and innate immunity in young Caenorhabditis elegans

Age-dependent heat shock hormesis to HSF-1 deficiency suggests a compensatory mechanism mediated by the unfolded protein response and innate immunity in young Caenorhabditis elegans

Age-dependent heat shock hormesis to HSF-1 deficiency suggests a compensatory mechanism mediated by the unfolded protein response and innate immunity in young Caenorhabditis elegans

The transcription factor HSF-1 (heat shock factor 1) acts as a master regulator of heat shock response in eukaryotic cells to maintain cellular proteostasis. The protein has a protective role in preventing cells from undergoing ageing, and neurodegeneration, and also mediates tumorigenesis. Thus, modulating HSF-1 activity in humans has a promising therapeutic potential for treating these pathologies. Loss of HSF-1 function is usually associated with impaired stress tolerance. Contrary to this conventional knowledge, we show here that inactivation of HSF-1 in the nematode Caenorhabditis elegans results in increased thermotolerance at young adult stages, whereas HSF-1 deficiency in animals passing early adult stages indeed leads to decreased thermotolerance, as compared to wild-type. Furthermore, a gene expression analysis supports that in young adults, distinct cellular stress response and immunity-related signaling pathways become induced upon HSF-1 deficiency. We also demonstrate that increased tolerance to proteotoxic stress in HSF-1-depleted young worms requires the activity of the unfolded protein response of the endoplasmic reticulum and the SKN-1/Nrf2-mediated oxidative stress response pathway, as well as an innate immunity-related pathway, suggesting a mutual compensatory interaction between HSF-1 and these conserved stress response systems. A similar compensatory molecular network is likely to also operate in higher animal taxa, raising the possibility of an unexpected outcome when HSF-1 activity is manipulated in humans.

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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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