1. RIOK2 phosphorylation by RSK promotes synthesis of the human small ribosomal subunit
- Author
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Yves Romeo, Carine Froment, Odile Burlet-Schiltz, Philippe P. Roux, Marie-Kerguelen Sarthou, Geneviève Lavoie, Charlotte Audoynaud, Thibault Houles, Maral Halladjian, Yves Henry, Sylvain Cantaloube, Oriane Lié, Emilie L. Cerezo, Anthony K. Henras, Unité de biologie moléculaire, cellulaire et du développement (MCD), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Montreal, QC, Canada] (Institute for Research in Immunology and Cancer), Université de Montréal (UdeM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
- Subjects
MAPK/ERK pathway ,Cell signaling ,Cancer Research ,Transcription, Genetic ,[SDV]Life Sciences [q-bio] ,Ribosome biogenesis ,Protein Synthesis ,Signal transduction ,QH426-470 ,Biochemistry ,Ribosome ,Substrate Specificity ,0302 clinical medicine ,Post-Translational Modification ,Phosphorylation ,Genetics (clinical) ,0303 health sciences ,Chemistry ,Kinase ,Signaling cascades ,Software Engineering ,Chemical Synthesis ,Precipitation Techniques ,Ribosome Subunits, Small ,Cell biology ,Nucleic acids ,Protein Transport ,Ribosomal RNA ,030220 oncology & carcinogenesis ,Engineering and Technology ,Cellular Structures and Organelles ,Mitogen-Activated Protein Kinases ,Research Article ,Computer and Information Sciences ,MAPK signaling cascades ,Biosynthetic Techniques ,Protein Serine-Threonine Kinases ,Biology ,Research and Analysis Methods ,Biosynthesis ,Computer Software ,03 medical and health sciences ,Genetics ,Immunoprecipitation ,Humans ,Non-coding RNA ,Protein kinase A ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Biology and Life Sciences ,Proteins ,HEK293 Cells ,Mutation ,RNA ,Ribosomes ,030217 neurology & neurosurgery - Abstract
Ribosome biogenesis lies at the nexus of various signaling pathways coordinating protein synthesis with cell growth and proliferation. This process is regulated by well-described transcriptional mechanisms, but a growing body of evidence indicates that other levels of regulation exist. Here we show that the Ras/mitogen-activated protein kinase (MAPK) pathway stimulates post-transcriptional stages of human ribosome synthesis. We identify RIOK2, a pre-40S particle assembly factor, as a new target of the MAPK-activated kinase RSK. RIOK2 phosphorylation by RSK stimulates cytoplasmic maturation of late pre-40S particles, which is required for optimal protein synthesis and cell proliferation. RIOK2 phosphorylation facilitates its release from pre-40S particles and its nuclear re-import, prior to completion of small ribosomal subunits. Our results bring a detailed mechanistic link between the Ras/MAPK pathway and the maturation of human pre-40S particles, which opens a hitherto poorly explored area of ribosome biogenesis., Author summary Ribosomes are universal molecular machines composed of ribosomal RNAs (rRNAs) and ribosomal proteins (RPs) responsible for the synthesis of cellular proteins. In eukaryotic cells, ribosome biogenesis relies on the assembly of large precursor particles (pre-ribosomes) containing, in addition to rRNAs and RPs, more than 200 accessory proteins named assembly and maturation factors (AMFs). Ribosome biogenesis is a highly energy demanding process which is tightly regulated to accommodate protein synthesis with cell growth requirements. In humans, the Ras/MAPK regulatory pathway is one of the main systems controlling cell growth and proliferation. Under favorable growth conditions, the Ras/MAPK pathway activates several aspects of ribosome production, such as synthesis of rRNAs and RPs. Our study highlights that the MAPK pathway also directly stimulates the assembly and maturation of pre-ribosomes. We identify the kinase RIOK2, an AMF involved in the synthesis of the small (40S) ribosomal subunit, as a new target of the MAPK-activated kinase RSK. We describe molecular events promoted by the MAPK pathway to finely tune the activity of RIOK2 during pre-40S particle maturation. This work is particularly important because of the current lack of mechanistic connections between growth-promoting signaling pathways and the assembly and maturation of pre-ribosomes in human cells.
- Published
- 2021