Calcineurin promotes adaptation to chronic stress through two distinct mechanisms.

IF 3.1 3区 生物学 Q3 CELL BIOLOGY Molecular Biology of the Cell Pub Date : 2024-10-01 Epub Date: 2024-07-31 DOI:10.1091/mbc.E24-03-0122
Mackenzie J Flynn, Nicholas W Harper, Rui Li, Lihua Julie Zhu, Michael J Lee, Jennifer A Benanti
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Abstract

Adaptation to environmental stress requires coordination between stress-defense programs and cell cycle progression. The immediate response to many stressors has been well characterized, but how cells survive in challenging environments long term is unknown. Here, we investigate the role of the stress-activated phosphatase calcineurin (CN) in adaptation to chronic CaCl2 stress in Saccharomyces cerevisiae. We find that prolonged exposure to CaCl2 impairs mitochondrial function and demonstrate that cells respond to this stressor using two CN-dependent mechanisms-one that requires the downstream transcription factor Crz1 and another that is Crz1 independent. Our data indicate that CN maintains cellular fitness by promoting cell cycle progression and preventing CaCl2-induced cell death. When Crz1 is present, transient CN activation suppresses cell death and promotes adaptation despite high levels of mitochondrial loss. However, in the absence of Crz1, prolonged activation of CN prevents mitochondrial loss and further cell death by upregulating glutathione biosynthesis genes thereby mitigating damage from reactive oxygen species. These findings illustrate how cells maintain long-term fitness during chronic stress and suggest that CN promotes adaptation in challenging environments by multiple mechanisms.

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钙调素通过两种不同的机制促进对慢性压力的适应。
对环境压力的适应需要压力防御程序和细胞周期进程之间的协调。细胞对许多应激源的即时反应已经得到了很好的描述,但细胞如何在具有挑战性的环境中长期存活却不得而知。在这里,我们研究了应激激活磷酸酶钙调磷酸酶(CN)在酿酒酵母适应慢性 CaCl2 应激中的作用。我们发现,长期暴露于 CaCl2 会损害线粒体功能,并证明细胞通过两种依赖 CN 的机制来应对这种应激,一种需要下游转录因子 Crz1,另一种则不依赖 Crz1。我们的数据表明,CN 通过促进细胞周期的进展和防止 CaCl2 诱导的细胞死亡来维持细胞的健康。当 Crz1 存在时,瞬时 CN 激活可抑制细胞死亡并促进适应,尽管线粒体损失水平很高。然而,在没有 Crz1 的情况下,CN 的长期激活可通过上调谷胱甘肽(GSH)生物合成基因防止线粒体丢失和细胞进一步死亡,从而减轻活性氧的损伤。这些发现说明了细胞如何在慢性应激过程中保持长期的适应性,并表明 CN 通过多种机制促进对挑战性环境的适应。
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来源期刊
Molecular Biology of the Cell
Molecular Biology of the Cell 生物-细胞生物学
CiteScore
6.00
自引率
6.10%
发文量
402
审稿时长
2 months
期刊介绍: MBoC publishes research articles that present conceptual advances of broad interest and significance within all areas of cell, molecular, and developmental biology. We welcome manuscripts that describe advances with applications across topics including but not limited to: cell growth and division; nuclear and cytoskeletal processes; membrane trafficking and autophagy; organelle biology; quantitative cell biology; physical cell biology and mechanobiology; cell signaling; stem cell biology and development; cancer biology; cellular immunology and microbial pathogenesis; cellular neurobiology; prokaryotic cell biology; and cell biology of disease.
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