Coccia Marta, Rossi Antonio, Riccio Anna, Trotta Edoardo, Santoro Maria Gabriella
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy.
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1045-1050. doi: 10.1073/pnas.1616112114. Epub 2017 Jan 17.
The nucleolus, a dynamic nuclear compartment long regarded as the cell ribosome factory, is emerging as an important player in the regulation of cell survival and recovery from stress. In larger eukaryotes, the stress-induced transcriptional response is mediated by a family of heat-shock transcription factors. Among these, HSF1, considered the master regulator of stress-induced transcriptional responses, controls the expression of cytoprotective heat shock proteins (HSPs), molecular chaperones/cochaperones constituting a major component of the cell protein quality control machinery essential to circumvent stress-induced degradation and aggregation of misfolded proteins. Herein we identify human NF-κB repressing factor (NKRF) as a nucleolar HSP essential for nucleolus homeostasis and cell survival under proteotoxic stress. NKRF acts as a thermosensor translocating from the nucleolus to the nucleoplasm during heat stress; nucleolar pools are replenished during recovery upon HSF1-mediated NKRF resynthesis. Silencing experiments demonstrate that NKRF is an unconventional HSP crucial for correct ribosomal RNA (rRNA) processing and preventing aberrant rRNA precursors and discarded fragment accumulation. These effects are mediated by NKRF interaction with the 5'-to-3' exoribonuclease XRN2, a key coordinator of multiple pre-rRNA cleavages, driving mature rRNA formation and discarded rRNA decay. Under stress conditions, NKRF directs XRN2 nucleolus/nucleoplasm trafficking, controlling 5'-to-3' exoribonuclease nucleolar levels and regulating rRNA processing. Our study reveals a different aspect of rRNA biogenesis control in human cells and sheds light on a sophisticated mechanism of nucleolar homeostasis surveillance during stress.
核仁，长期以来一直被视为细胞核糖体工厂的一个动态核区室，正逐渐成为细胞存活和应激恢复调节中的一个重要参与者。在较大的真核生物中，应激诱导的转录反应由一组热休克转录因子介导。其中，HSF1被认为是应激诱导转录反应的主要调节因子，它控制细胞保护热休克蛋白（HSPs）的表达，分子伴侣/共伴侣构成细胞蛋白质质量控制机制的主要成分，对于规避应激诱导的错误折叠蛋白降解和聚集至关重要。在此，我们鉴定出人类NF-κB抑制因子（NKRF）是一种核仁HSP，对于蛋白毒性应激下的核仁稳态和细胞存活至关重要。NKRF作为一种热传感器，在热应激期间从核仁转移到核质；在HSF1介导的NKRF重新合成后恢复过程中，核仁池得到补充。沉默实验表明，NKRF是一种非常规HSP，对于正确的核糖体RNA（rRNA）加工以及防止异常rRNA前体和废弃片段积累至关重要。这些作用是由NKRF与5'-至-3'外切核糖核酸酶XRN2相互作用介导的，XRN2是多个前体rRNA切割的关键协调者，驱动成熟rRNA形成和废弃rRNA降解。在应激条件下，NKRF指导XRN2的核仁/核质运输，控制5'-至-3'外切核糖核酸酶的核仁水平并调节rRNA加工。我们的研究揭示了人类细胞中rRNA生物合成控制的一个不同方面，并阐明了应激期间核仁稳态监测的复杂机制。
