A Mitochondrial Stress-Specific Form of HSF1 Protects against Age-Related Proteostasis Collapse.
A Mitochondrial Stress-Specific Form of HSF1 Protects against Age-Related Proteostasis Collapse.
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DOI：
10.1016/j.devcel.2020.06.038
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发表时间：
2020-07
影响因子：
11.8
通讯作者：
Rhianna Williams;Mihails Laskovs;Rebecca Williams;Ananya Mahadevan;Johnathan Labbadia
中科院分区：
文献类型：
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作者：
Rhianna Williams;Mihails Laskovs;Rebecca Williams;Ananya Mahadevan;Johnathan Labbadia
蛋白质稳态的丧失（蛋白质稳态）是年龄相关组织功能障碍的主要驱动因素。最近的研究表明，随着年龄的增长，蛋白质稳态的失败是由发育和生殖线索引发的，这些线索抑制了成年早期蛋白质稳态相关途径的活性。在秀丽隐杆线虫中，发育过程中线粒体电子传递链（ETC）功能的降低可以覆盖促进衰老组织中蛋白质稳态崩溃的信号。然而，目前还不清楚这些有益的效果是如何介导的。在这里，我们发现，在响应ETC损伤，PP 2A复合物产生一个去磷酸化，线粒体应激特异性的转录因子HSF-1的变体。这导致在成年期选择性诱导小的热休克蛋白，从而防止与年龄相关的蛋白质稳态崩溃。我们认为，生命早期的线粒体信号可以通过调整HSF-1的活性来优先驱动非ATP依赖性伴侣蛋白的表达，从而保护衰老的细胞溶质蛋白质组。
The loss of protein homeostasis (proteostasis) is a primary driver of age-related tissue dysfunction. Recent studies have revealed that the failure of proteostasis with age is triggered by developmental and reproductive cues that repress the activity of proteostasis-related pathways in early adulthood. InCaenorhabditis elegans, reduced mitochondrial electron transport chain (ETC) function during development can override signals that promote proteostasis collapse in aged tissues. However, it is unclear precisely how these beneficial effects are mediated. Here, we reveal that in response to ETC impairment, the PP2A complex generates a dephosphorylated, mitochondrial stress-specific variant of the transcription factor HSF-1. This results in the selective induction of small heat shock proteins in adulthood, thereby protecting against age-related proteostasis collapse. We propose that mitochondrial signals early in life can protect the aging cytosolic proteome by tailoring HSF-1 activity to preferentially drive the expression of non-ATP-dependent chaperones.