Spatial control of nucleoporin assembly 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 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.\n\nHighlightsCytoplasmic nucleoporins are assembled by Fragile X-related (FXR) proteins and dynein\n\nFXR-Dynein pathway downregulation induces aberrant cytoplasmic aggregation of nucleoporins\n\nCellular models of Fragile X syndrome accumulate aberrant cytoplasmic nucleoporin aggregates.\n\nFXR-Dynein pathway regulates nuclear morphology and G1 cell cycle progression\n\neTOC BlurbNucleoporins (Nups) form Nuclear Pore Complexes (NPCs) at the nuclear envelope. Agote-Aran 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.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC=\"FIGDIR/small/767202v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (29K):\norg.highwire.dtl.DTLVardef@14a684borg.highwire.dtl.DTLVardef@53670org.highwire.dtl.DTLVardef@391907org.highwire.dtl.DTLVardef@9a290a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG