biostudies-literatureUnknownLinsenmeier MNIA NIH HHSNINDS NIH HHSNIGMS NIH HHSRNA-binding proteins (RBPs) with prion-like domains, including FUS, hnRNPA1, and hnRNPA2, assemble into functional, metastable condensates that organize ribostasis, but can also transition into self-templating fibrils implicated in neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS). How nuclear-import receptors (NIRs) antagonize this pathological transition has remained unresolved. Here, we establish that NIRs regulate the phase behavior of prion-like cargos by remodeling the dilute phase. Quantitative analyses across length scales reveal that Karyopherin-β2 (Kapβ2) preferentially binds cargo in the dilute phase to lower the effective concentration of free RBPs thereby elevating the saturation concentration for phase separation and suppressing mesoscale clusterinbioRxiv : the preprint server for biology2025.11.14.688546https://www.ebi.ac.uk/biostudies/studies/S-EPMC12642399biostudies-literatureNuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.PMC12642399R01 AG077771K99 GM152778R01 NS121114R35 GM138211Bugaj LJMumford TRPappu RVShorter JShinn MKLinsenmeier MLiu VfalseNuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.RNA-binding proteins (RBPs) with prion-like domains, including FUS, hnRNPA1, and hnRNPA2, assemble into functional, metastable condensates that organize ribostasis, but can also transition into self-templating fibrils implicated in neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS). How nuclear-import receptors (NIRs) antagonize this pathological transition has remained unresolved. Here, we establish that NIRs regulate the phase behavior of prion-like cargos by remodeling the dilute phase. Quantitative analyses across length scales reveal that Karyopherin-β2 (Kapβ2) preferentially binds cargo in the dilute phase to lower the effective concentration of free RBPs thereby elevating the saturation concentration for phase separation and suppressing mesoscale clusterin2025-01-01T00:00:00Z2025 Nov2026-06-02T03:17:52.919Z2026-06-02T03:09:02.449ZS-EPMC126423994129277310.1101/2025.11.14.688546