title: Human NF-κB repressing factor acts as a stress-regulated switch for ribosomal RNA processing and nucleolar homeostasis surveillance.
abstract: 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.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.|Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Coccia
authors.affiliation: Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.|Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Riccio
authors.affiliation: Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Trotta
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy; santoro@uniroma2.it.|Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Santoro
mesh_terms: D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D000076249:Heat Shock Transcription Factors / Q000502:physiology; D006706:Homeostasis; D006358:Hot Temperature; D006801:Humans; D001678:Organelle Biogenesis; D021381:Protein Transport; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D012335:RNA, Ribosomal / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D012270:Ribosomes / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C111027:NKRF protein, human; D012335:RNA, Ribosomal; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D003609:Dactinomycin; D004247:DNA
keywords: NF-kappaB; heat shock factor 1; nucleolus; proteotoxic stress; rRNA processing