title: Impairing the production of ribosomal RNA activates mammalian target of rapamycin complex 1 signalling and downstream translation factors.
abstract: Ribosome biogenesis is a key process for maintaining protein synthetic capacity in dividing or growing cells, and requires coordinated production of ribosomal proteins and ribosomal RNA (rRNA), including the processing of the latter. Signalling through mammalian target of rapamycin complex 1 (mTORC1) activates all these processes. Here, we show that, in human cells, impaired rRNA processing, caused by expressing an interfering mutant of BOP1 or by knocking down components of the PeBoW complex elicits activation of mTORC1 signalling. This leads to enhanced phosphorylation of its substrates S6K1 and 4E-BP1, and stimulation of proteins involved in translation initiation and elongation. In particular, we observe both inactivation and downregulation of the eukaryotic elongation factor 2 kinase, which normally inhibits translation elongation. The latter effect involves decreased expression of the eEF2K mRNA. The mRNAs for ribosomal proteins, whose translation is positively regulated by mTORC1 signalling, also remain associated with ribosomes. Therefore, our data demonstrate that disrupting rRNA production activates mTORC1 signalling to enhance the efficiency of the translational machinery, likely to help compensate for impaired ribosome production.
authors: Centre for Biological Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK, Centre de Recherche en Nutrition Humaine, INRA Clermont-Theix, Unité de Nutrition Humaine, 63122 Ceyrat, France and Division of Molecular Physiology, James Black Centre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
authors: Rui
authors: R
authors: Liu
authors: Valentina
authors: V
authors: Iadevaia
authors: Julien
authors: J
authors: Averous
authors: Peter M
authors: PM
authors: Taylor
authors: Ze
authors: Z
authors: Zhang
authors: Christopher G
authors: CG
authors: Proud
mesh_terms: D002460:Cell Line; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010445:Peptide Elongation Factors / Q000378:metabolism; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D016601:RNA-Binding Proteins; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C514383:BOP1 protein, human; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D011506:Proteins; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D054736:Elongation Factor 2 Kinase