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Spatial control of nucleoporin assembly by Fragile X-related proteins

Arantxa Agote-Arán, Stephane Schmucker, Katerina Jerabkova, Inès Jmel Boyer, Alessandro Berto, Laura Pacini, Paolo Ronchi, Charlotte Kleiss, Laurent Guerard, Yannick Schwab, Hervé Moine, Jean-Louis Mandel, Sebastien Jacquemont, Claudia Bagni, Izabela Sumara
doi: https://doi.org/10.1101/767202
Arantxa Agote-Arán
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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Stephane Schmucker
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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Katerina Jerabkova
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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Inès Jmel Boyer
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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Alessandro Berto
5Institut Jacques Monod, CNRS UMR7592-Université Paris Diderot, Sorbonne Paris Cité, Paris, France
6Ecole Doctorale SDSV, Université Paris Sud, Orsay, France
14Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
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Laura Pacini
7Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
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Paolo Ronchi
8European Molecular Biology Laboratory, Electron Microscopy Core Facility, Heidelberg, Germany
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Charlotte Kleiss
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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Laurent Guerard
9Imaging Core Facility, Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland
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Yannick Schwab
8European Molecular Biology Laboratory, Electron Microscopy Core Facility, Heidelberg, Germany
10European Molecular Biology Laboratory, European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Heidelberg, Germany
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Hervé Moine
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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Jean-Louis Mandel
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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Sebastien Jacquemont
11Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, 1011 Lausanne, University of Lausanne, Switzerland
12CHU Sainte-Justine Research Centre, University of Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada
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Claudia Bagni
7Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
13Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland
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Izabela Sumara
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
2Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France
3Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France
4Université de Strasbourg, Strasbourg, France
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  • For correspondence: sumara@igbmc.fr
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Summary

Nucleoporins (Nups) build highly organized Nuclear Pore Complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs to regulate nucleocytoplasmic exchange. In the cytoplasm, a large excess of soluble Nups has been reported, but how their assembly is restricted to the NE is currently unknown. Here we show that Fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule and dynein-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and Fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup protein condensates. Likewise, several models of Fragile X syndrome (FXS), characterized by a loss of FMRP, also accumulate cytoplasmic Nup aggregates. These aggregate-containing cells display aberrant nuclear morphology and a delay in G1 cell cycle progression. Our results reveal an unexpected role for the FXR protein family and dynein in the spatial regulation of nucleoporin assembly.

Highlights Cytoplasmic nucleoporins are assembled by Fragile X-related (FXR) proteins and dynein

FXR-Dynein pathway downregulation induces aberrant cytoplasmic aggregation of nucleoporins

Cellular models of Fragile X syndrome accumulate aberrant cytoplasmic nucleoporin aggregates.

FXR-Dynein pathway regulates nuclear morphology and G1 cell cycle progression

eTOC Blurb Nucleoporins (Nups) form Nuclear Pore Complexes (NPCs) at the nuclear envelope. Agote-Arán at al. show how cells inhibit aberrant assembly of Nups in the cytoplasm and identify Fragile X-related (FXR) proteins and dynein that facilitate localization of Nups to the nuclear envelope and control G1 cell cycle progression.

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Posted September 12, 2019.
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Spatial control of nucleoporin assembly by Fragile X-related proteins
Arantxa Agote-Arán, Stephane Schmucker, Katerina Jerabkova, Inès Jmel Boyer, Alessandro Berto, Laura Pacini, Paolo Ronchi, Charlotte Kleiss, Laurent Guerard, Yannick Schwab, Hervé Moine, Jean-Louis Mandel, Sebastien Jacquemont, Claudia Bagni, Izabela Sumara
bioRxiv 767202; doi: https://doi.org/10.1101/767202
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Spatial control of nucleoporin assembly by Fragile X-related proteins
Arantxa Agote-Arán, Stephane Schmucker, Katerina Jerabkova, Inès Jmel Boyer, Alessandro Berto, Laura Pacini, Paolo Ronchi, Charlotte Kleiss, Laurent Guerard, Yannick Schwab, Hervé Moine, Jean-Louis Mandel, Sebastien Jacquemont, Claudia Bagni, Izabela Sumara
bioRxiv 767202; doi: https://doi.org/10.1101/767202

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