The ribosome-associated protein RACK1 represses Kir4.1 translation in astrocytes and influences neuronal activity

  • Cell Rep. 2023 Apr 30;42(5):112456. doi: 10.1016/j.celrep.2023.112456.
Marc Oudart  1 ,  Katia Avila-Gutierrez  1 ,  Clara Moch  2 ,  Elena Dossi  1 ,  Giampaolo Milior  1 ,  Anne-Cécile Boulay  1 ,  Mathis Gaudey  1 ,  Julien Moulard  1 ,  Bérangère Lombard  3 ,  Damarys Loew  3 ,  Alexis-Pierre Bemelmans  4 ,  Nathalie Rouach  1 ,  Clément Chapat  2 ,  Martine Cohen-Salmon  5
Affiliations
  • 1. Center for Interdisciplinary Research in Biology, College de France, CNRS, INSERM, Université PSL, Labex Memolife, Paris, France.
  • 2. Laboratoire de Biochimie, Ecole Polytechnique, CNRS, Université Paris-Saclay, Palaiseau, France.
  • 3. CurieCoreTech Spectrométrie de Masse Protéomique, Institut Curie, University PSL, Paris, France.
  • 4. CEA, Institut de Biologie François Jacob, Molecular Imaging Research Center (MIRCen), CNRS, Université Paris-Sud, Université Paris-Saclay, Fontenay-aux-Roses, France.
  • 5. Center for Interdisciplinary Research in Biology, College de France, CNRS, INSERM, Université PSL, Labex Memolife, Paris, France. Electronic address: [email protected].
PMID: 37126448 DOI: 10.1016/j.celrep.2023.112456
Abstract

The regulation of translation in astrocytes, the main glial cells in the brain, remains poorly characterized. We developed a high-throughput proteomics screen for polysome-associated proteins in astrocytes and focused on ribosomal protein receptor of activated protein C kinase 1 (RACK1), a critical factor in translational regulation. In astrocyte somata and perisynaptic astrocytic processes (PAPs), RACK1 preferentially binds to a number of mRNAs, including Kcnj10, encoding the inward-rectifying potassium (K+) channel Kir4.1. By developing an astrocyte-specific, conditional RACK1 knockout mouse model, we show that RACK1 represses production of Kir4.1 in hippocampal astrocytes and PAPs. Upregulation of Kir4.1 in the absence of RACK1 increases astrocytic Kir4.1-mediated K+ currents and volume. It also modifies neuronal activity attenuating burst frequency and duration. Reporter-based assays reveal that RACK1 controls Kcnj10 translation through the transcript's 5' untranslated region. Hence, translational regulation by RACK1 in astrocytes represses Kir4.1 expression and influences neuronal activity.

Keywords
CP: Neuroscience; K(+)current; Kir4.1; RACK1; astrocytes; neuroglial interactions; neurotransmission; ribosome; translation.
Products