The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress [ChIP-seq]

Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how different layers of UPRmt regulators are orchestrated to transcriptionally activate the stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator for UPRmt activation, as well as for mitochondrial stress-induced immune response, amyloid-β aggregation reduction and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300. N2 worms carrying a hsp-6::GFP reporter fed with control or cco-1 RNAi, and ChIP with H3K18Ac or H3K27Ac

生物体通过激活包括线粒体未折叠蛋白反应（mitochondrial unfolded protein response，UPRmt）在内的多种防御通路，以应对线粒体应激。然而，目前对于如何协调不同层级的UPRmt调控因子，从而转录激活应激反应的机制仍不甚明确。本研究鉴定出CBP-1，即哺乳动物乙酰转移酶CBP/p300在线虫中的同源蛋白，其不仅是UPRmt激活的关键调控因子，同时在秀丽隐杆线虫（Caenorhabditis elegans）中，该蛋白还参与介导线粒体应激诱导的免疫反应、淀粉样β蛋白（amyloid-β）聚集减少以及寿命延长过程。机制层面，CBP-1作用于组蛋白去甲基化酶JMJD-1.2/JMJD-3.1的下游，以及包括ATFS-1在内的UPRmt转录因子的上游，由此系统性诱导广谱UPRmt基因的表达，并执行多种有益功能。在小鼠与人类群体中，CBP/p300的转录水平与UPRmt相关转录本及寿命呈正相关。此外，抑制CBP/p300会破坏哺乳动物细胞中的UPRmt，而强制过表达p300则足以激活该通路。上述研究结果揭示了一种进化保守的机制，该机制通过CBP/p300调控线粒体应激反应，进而促进机体健康与寿命延长。本研究涉及的实验材料包括携带hsp-6::GFP报告基因的N2线虫（分别喂食对照RNA干扰（RNAi）或cco-1 RNAi），以及采用H3K18Ac或H3K27Ac进行的染色质免疫沉淀（ChIP）实验样本。