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 Caenorhabditiselegans. 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.
Highlights
The primary function of the nucleolus is ribosome biogenesis, which is an extremely energetically expensive process
We showed that nucleolar stress induced by genetic mutations in rsks-1, pro-2, and pro-3, as well as inhibition of rDNA transcription using actinomycin D (AD), leads to excessive lipid accumulation
The present study revealed that nucleolar stress elicited by gene mutations in rsks-1, rrp-8, pro-2, and pro-3 participates in pre-ribosomal RNA (rRNA) processing and the AD treatment blocks pre-rRNA transcription, consistently leading to excessive lipid accumulation in C. elegans
Summary
The primary function of the nucleolus is ribosome biogenesis, which is an extremely energetically expensive process. Failures in ribosome biogenesis or function result in a condition termed nucleolar stress, which leads to disruptions in cell homeostasis[4,5]. More than half of human cancers lack functional p53, non-mammalian systems such as yeast lack p53, and both Caenorhabditis elegans and Drosophila lack MDM2, these organisms possess p53 These data argue that other p53-independent nuclear stress pathways may be evolutionarily conserved or markedly vary across eukaryotes. ENoSC may act as a sensor in the nucleolus connecting intracellular energy status with p53 activation[11,12] These studies demonstrate that nucleolar stress triggered by the perturbation of ribosome biogenesis can force the cell to shift its energy status and eventually alter lipid homeostasis. The underlying mechanisms linking nucleolar stress and lipid accumulation remain largely unknown
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