Nucleoporin Nsp1 surveils the phase state of FG-Nups

• Published in: Cell reports (Cambridge) 2024-10, Vol.43 (10), p.114793, Article 114793
• Main Authors: Otto, Tegan A., Bergsma, Tessa, Dekker, Maurice, Mouton, Sara N., Gallardo, Paola, Wolters, Justina C., Steen, Anton, Onck, Patrick R., Veenhoff, Liesbeth M.
• Format: Article
• Language: English
• Subjects: aging; chaperones; condensate; CP: Molecular biology; FG-nucleoporin; intrinsically disordered protein; Kap95; liquid-liquid phase separation; nsp1; nuclear pore complex; protein homeostasis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114793

Transport through the nuclear pore complex (NPC) relies on intrinsically disordered FG-nucleoporins (FG-Nups) forming a selective barrier. Away from the NPC, FG-Nups readily form condensates and aggregates, and we address how this behavior is surveilled in cells. FG-Nups, including Nsp1, together with the nuclear transport receptor Kap95, form a native daughter cell-specific cytosolic condensate in yeast. In aged cells, this condensate disappears as cytosolic Nsp1 levels decline. Biochemical assays and modeling show that Nsp1 is a modulator of FG-Nup condensates, promoting a liquid-like state. Nsp1’s presence in the cytosol and condensates is critical, as a reduction of cytosolic levels in young cells induces NPC defects and a general decline in protein quality control that quantitatively mimics aging phenotypes. These phenotypes can be rescued by a cytosolic form of Nsp1. We conclude that Nsp1 is a phase state regulator that surveils FG-Nups and impacts general protein homeostasis. [Display omitted] •Nups form native cytosolic condensates•Nsp1 reduction mimics nuclear pore complex aging phenotypes•Nsp1 acts as phase-state modulator of FG-Nups•Nsp1 shares surveillance function with classical chaperones Here, Otto et al. address how the reduced expression of the intrinsically disordered FG-nucleoporin Nsp1 in aged cells relates to age-related nuclear pore complex assembly problems. They find that Nsp1 acts as a phase-state modulator, promoting a liquid-like state of FG-nucleoporin condensates and impacting general protein homeostasis.