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Karyopherin enrichment and compensation fortifies the nuclear pore complex against nucleocytoplasmic leakage
Journal
Journal of Cell Biology
Volume
221
Number
3
Pages / Article-Number
e202108107
Mesh terms
Animals; Binding, Competitive; Cell Membrane Permeability; Diffusion; Dogs; Fluorescence Recovery After Photobleaching; Gene Deletion; HeLa Cells; Humans; Karyopherins, metabolism; Madin Darby Canine Kidney Cells; Nuclear Pore, metabolism; Protein Binding; Protein Domains
Abstract
Nuclear pore complexes (NPCs) discriminate nonspecific macromolecules from importin and exportin receptors, collectively termed "karyopherins" (Kaps), that mediate nucleocytoplasmic transport. This selective barrier function is attributed to the behavior of intrinsically disordered phenylalanine-glycine nucleoporins (FG Nups) that guard the NPC channel. However, NPCs in vivo are typically enriched with different Kaps, and how they impact the NPC barrier remains unknown. Here, we show that two major Kaps, importinβ1/karyopherinβ1 (Kapβ1) and exportin 1/chromosomal maintenance 1 (CRM1), are required to fortify NPC barrier function in vivo. Their enrichment at the NPC is sustained by promiscuous binding interactions with the FG Nups, which enable CRM1 to compensate for the loss of Kapβ1 as a means to maintain NPC barrier function. However, such a compensatory mechanism is constrained by the cellular abundances and different binding kinetics for each respective Kap, as evidenced for importin-5. Consequently, we find that NPC malfunction and nucleocytoplasmic leakage result from poor Kap enrichment.
