Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
Human Health Therapeutics, National Research Council Canada, 100 Sussex Drive, Ottawa, ON, K1N 5A2, Canada.
Cell Death Differ. 2019 Dec;26(12):2637-2651. doi: 10.1038/s41418-019-0325-6. Epub 2019 Apr 5.
Apoptosis is a genetically programmed cell death process with profound roles in development and disease. MicroRNAs modulate the expression of many proteins and are often deregulated in human diseases, such as cancer. C. elegans germ cells undergo apoptosis in response to genotoxic stress by the combined activities of the core apoptosis and MAPK pathways, but how their signalling thresholds are buffered is an open question. Here we show mir-35-42 miRNA family play a dual role in antagonizing both NDK-1, a positive regulator of MAPK signalling, and the BH3-only pro-apoptotic protein EGL-1 to regulate the magnitude of DNA damage-induced apoptosis in the C. elegans germline. We show that while miR-35 represses EGL-1 by promoting transcript degradation, repression of NDK-1 may be through sequestration of the transcript to inhibit translation. Importantly, dramatic increase in NDK-1 expression was observed in cells about to die. In the absence of miR-35, increased NDK-1 activity enhanced MAPK signalling that lead to significant increases in germ cell death. Our findings demonstrate that NDK-1 acts upstream of (or in parallel to) EGL-1, and that miR-35 targets both egl-1 and ndk-1 to fine-tune cell killing in response to genotoxic stress.
细胞凋亡是一种具有重要发育和疾病作用的基因程序性细胞死亡过程。microRNAs 调节许多蛋白质的表达，并且经常在人类疾病中失调，例如癌症。线虫生殖细胞通过核心凋亡和 MAPK 途径的联合活性对遗传毒性应激发生凋亡，但它们的信号阈值如何被缓冲是一个悬而未决的问题。在这里，我们表明 mir-35-42 miRNA 家族在拮抗 NDK-1（MAPK 信号的正调节剂）和 BH3 仅促凋亡蛋白 EGL-1 方面发挥双重作用，以调节线虫生殖细胞中 DNA 损伤诱导的凋亡程度。我们表明，虽然 mir-35 通过促进转录降解来抑制 EGL-1，但对 NDK-1 的抑制可能是通过将转录物隔离以抑制翻译来实现的。重要的是，在即将死亡的细胞中观察到 NDK-1 表达的急剧增加。在没有 mir-35 的情况下，增加的 NDK-1 活性增强了 MAPK 信号，导致生殖细胞死亡显著增加。我们的研究结果表明，NDK-1 在线虫生殖细胞中发挥作用，在遗传毒性应激下，mir-35 靶向 egl-1 和 ndk-1 以微调细胞杀伤。
