The primary function of the nucleolus is ribosome biogenesis, which is an extremely energetically expensive process. Failures in ribosome biogenesis cause nucleolar stress with an altered energy status. However, little is known about the underlying mechanism linking nucleolar stress to energy metabolism. Here we show that nucleolar stress is triggered by inactivation of RSKS-1 (ribosomal protein S6 kinase), RRP-8 (ribosomal RNA processing 8), and PRO-2/3 (proximal proliferation), all of which are involved in ribosomal RNA processing or inhibition of rDNA transcription by actinomycin D (AD), leading to excessive lipid accumulation in Caenorhabditis elegans. The transcription factor PHA-4/FoxA acts as a sensor of nucleolar stress to bind to and transactivate the expression of the lipogenic genes pod-2 (acetyl-CoA carboxylase), fasn-1 (fatty acid synthase), and dgat-2 (diacylglycerol O-acyltransferase 2), consequently promoting lipid accumulation. Importantly, inactivation of pha-4 or dgat-2 is sufficient to abolish nucleolar stress-induced lipid accumulation and prolonged starvation survival. The results revealed a distinct PHA-4-mediated lipogenesis pathway that senses nucleolar stress and shifts excessive energy for storage as fat.

中文翻译：

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PHA-4/FoxA 感知核仁应激以调节秀丽隐杆线虫中的脂质积累。

核仁的主要功能是核糖体生物合成，这是一个极其耗费能量的过程。核糖体生物发生的失败会导致核仁应激并改变能量状态。然而，人们对核仁应激与能量代谢之间的潜在机制知之甚少。在这里，我们表明核仁应激是由 RSKS-1（核糖体蛋白 S6 激酶）、RRP-8（核糖体 RNA 加工 8）和 PRO-2/3（近端增殖）失活触发的，所有这些都参与核糖体 RNA放线菌素 D (AD) 加工或抑制 rDNA 转录，导致秀丽隐杆线虫体内脂质过度积累。转录因子 PHA-4/FoxA 作为核仁应激传感器，与脂肪生成基因 pod-2（乙酰辅酶 A 羧化酶）、fasn-1（脂肪酸合酶）和 dgat-2 结合并反式激活其表达。二酰基甘油O-酰基转移酶2)，从而促进脂质积累。重要的是，pha-4 或 dgat-2 的失活足以消除核仁应激诱导的脂质积累和延长饥饿生存。结果揭示了一种独特的 PHA-4 介导的脂肪生成途径，该途径可感知核仁应激并将过多的能量转移为脂肪储存。