Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Laboratory of Metabolic Signaling, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Nat Aging. 2021 Feb;1(2):165-178. doi: 10.1038/s43587-020-00025-z. Epub 2021 Feb 8.
Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPR). However, how UPR regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPR, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in . Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPR transcription factors including ATFS-1, to systematically induce a broad spectrum of UPR genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of positively correlate with UPR transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPR in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.
生物体通过激活多种防御途径来应对线粒体应激，包括线粒体未折叠蛋白反应（UPR）。然而，UPR 调节因子如何协调转录激活应激反应在很大程度上仍然未知。在这里，我们鉴定出 CBP-1，即哺乳动物乙酰转移酶 CBP/p300 的线虫同源物，作为 UPR 以及线粒体应激诱导的免疫反应、减少淀粉样β聚集和延长 的必需调节剂。在机制上，CBP-1 作为组蛋白去甲基酶 JMJD-1.2/JMJD-3.1 的下游和 UPR 转录因子（包括 ATFS-1）的上游发挥作用，系统地上调广泛的 UPR 基因并执行多种有益功能。在小鼠和人类群体中， 的转录水平与 UPR 转录物和寿命呈正相关。此外，CBP/p300 的抑制破坏了，而 p300 的强制表达足以激活哺乳动物细胞中的 UPR。这些结果突出了一种进化上保守的机制，该机制决定了线粒体应激反应，并通过 CBP/p300 促进健康和长寿。
