Spatial control of nucleoporin condensation by fragile X‐related proteins

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. In the cytoplasm, the soluble Nups exist, but how their assembly is restricted to the NE is currently unknow...

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Vydané v:	The EMBO journal Ročník 39; číslo 20; s. e104467 - n/a
Hlavní autori:	Agote‐Aran, Arantxa, Schmucker, Stephane, Jerabkova, Katerina, Jmel Boyer, Inès, Berto, Alessandro, Pacini, Laura, Ronchi, Paolo, Kleiss, Charlotte, Guerard, Laurent, Schwab, Yannick, Moine, Hervé, Mandel, Jean‐Louis, Jacquemont, Sebastien, Bagni, Claudia, Sumara, Izabela
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 15.10.2020 Springer Nature B.V EMBO Press John Wiley and Sons Inc
Predmet:	Acrylates - pharmacology Animals Cell cycle Cell Line Cell morphology Cell Nucleus - metabolism Condensates Condensation Cytology Cytoplasm Cytoplasm - drug effects Cytoplasm - metabolism Down-Regulation Dynein EMBO20 FMR1 protein Fragile X Mental Retardation Protein - genetics Fragile X Mental Retardation Protein - metabolism Fragile X syndrome Fragile X Syndrome - genetics Fragile X Syndrome - metabolism FXR1 G1 phase G1 Phase Cell Cycle Checkpoints - genetics Granular materials Humans Hydrogels In Situ Hybridization, Fluorescence Intellectual disabilities Interphase - genetics Life Sciences Localization Mice Microscopy, Electron, Transmission Microtubules - drug effects Microtubules - metabolism Microtubules - ultrastructure Morphology Myoblasts - drug effects Myoblasts - metabolism Nuclear Envelope - drug effects Nuclear Envelope - metabolism Nuclear Envelope - ultrastructure Nuclear Pore Complex Proteins - genetics Nuclear Pore Complex Proteins - metabolism Nucleoporins Phase separation Protein transport Proteins RNA, Small Interfering RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism dynein FXR1 phase separation nucleoporins fragile X syndrome phase separation Subject Category Membrane & Trafficking
ISSN:	0261-4189, 1460-2075, 1460-2075
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Shrnutí:	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. In the cytoplasm, the soluble Nups exist, 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‐dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup condensates. Likewise, models of fragile X syndrome (FXS), characterized by a loss of FMRP, accumulate Nup granules. The Nup granule‐containing cells show defects in protein export, nuclear morphology and cell cycle progression. Our results reveal an unexpected role for the FXR protein family in the spatial regulation of nucleoporin condensation. Synopsis Fragile X‐related proteins and dynein inhibit ectopic phase separation of nucleoporins in the cytoplasm and facilitate their localization to the nuclear envelope during G1 phase of the cell cycle. Fragile X‐related (FXR) proteins and dynein regulate localization of cytoplasmic nucleoporins. FXR‐Dynein pathway downregulation induces aberrant cytoplasmic condensation of nucleoporins. Cellular models of Fragile X syndrome accumulate aberrant cytoplasmic nucleoporin condensates. FXR‐Dynein pathway regulates nuclear morphology and cell cycle progression. Graphical Abstract Fragile X‐related proteins and dynein inhibit ectopic phase separation of nucleoporins in the cytoplasm and facilitate their localization to the nuclear envelope during G1 phase of the cell cycle.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7560220 These authors contributed equally to this work
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.2020104467