Nucleoporin Nsp1 surveils the phase state of FG-Nups
Tegan A. Otto,
Tessa Bergsma,
Maurice Dekker,
Sara N. Mouton,
Paola Gallardo,
Justina C. Wolters,
Anton Steen,
Patrick R. Onck,
Liesbeth M. Veenhoff
Affiliations
Tegan A. Otto
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands
Tessa Bergsma
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands
Maurice Dekker
Zernike Institute for Advanced Materials, University of Groningen, 9747AG Groningen, the Netherlands
Sara N. Mouton
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands
Paola Gallardo
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands
Justina C. Wolters
Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands
Anton Steen
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands
Patrick R. Onck
Zernike Institute for Advanced Materials, University of Groningen, 9747AG Groningen, the Netherlands
Liesbeth M. Veenhoff
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713AV Groningen, the Netherlands; Corresponding author
Summary: 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.
