European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands.
Zernike Institute for Advanced Materials, University of Groningen, 9747AG Groningen, the Netherlands.
Cell Rep. 2024 Oct 22;43(10):114793. doi: 10.1016/j.celrep.2024.114793. Epub 2024 Oct 1.
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.
核孔复合物（NPC）的转运依赖于固有无序的 FG-Nup（FG-Nups）形成选择性屏障。在 NPC 之外，FG-Nups 很容易形成凝聚物和聚集体，我们研究了细胞如何对此进行监控。FG-Nups，包括 Nsp1，与核转运受体 Kap95 一起，在酵母中形成一种天然的子细胞特异性细胞质凝聚物。在衰老的细胞中，随着细胞质 Nsp1 水平的下降，这种凝聚物消失了。生化分析和建模表明，Nsp1 是 FG-Nup 凝聚物的调节剂，促进液体样状态。Nsp1 在细胞质和凝聚物中的存在是至关重要的，因为年轻细胞中细胞质水平的降低会导致 NPC 缺陷和蛋白质质量控制的普遍下降，这在数量上模拟了衰老表型。这些表型可以通过细胞质形式的 Nsp1 来挽救。我们得出结论，Nsp1 是一种相位状态调节剂，可监控 FG-Nups 并影响一般蛋白质的动态平衡。
