转录因子PHA-4/FoxA可调节线虫的脂质积累

Title：
PHA-4/FoxA senses nucleolar stress to regulate lipid accumulation in Caenorhabditis elegans

DOI：
10.1038/s41467-018-03531-2

Abstract：
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.

All Authors：
Jieyu Wu,Xue Jiang,Yamei Li,Tingting Zhu,Jingjing Zhang,Zhiguo Zhang,Linqiang Zhang,Yuru Zhang,Yanli Wang,Xiaoju Zou,Bin Liang

First Authors：
Jieyu Wu

Correspondence：
Xiaoju Zou,Bin Liang

摘要：

      核糖体生物合成失败会导致伴随着能量状态改变的核仁应激；RSKS-1、RRP-8和PRO-2/3的失活通过放线菌素D（AD）参与核糖体RNA（rRNA）加工或抑制rDNA转录，触发核仁应激，导致在秀丽隐杆线虫中脂质积累； 转录因子PHA-4/FoxA作为核仁应激的传感器，结合并反式激活脂肪生成基因pod-2、fasn-1和dgat-2的表达，随后促进脂质积累；pha-4或dgat-2失活足够消除核仁应激诱导的脂质积累和延长的饥饿存活。