Taniguchi Reiya, Orniacki Clarisse, Kreysing Jan Philipp, Zila Vojtech, Zimmerli Christian E, Böhm Stefanie, Turoňová Beata, Kräusslich Hans-Georg, Doye Valérie, Beck Martin
Department of Molecular Sociology, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.
RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Japan.
Nat Cell Biol. 2025 May;27(5):762-775. doi: 10.1038/s41556-025-01648-3. Epub 2025 Apr 9.
Nuclear pore complexes (NPCs) mediate nucleocytoplasmic exchange, which is essential for eukaryotes. Mutations in the central scaffolding components of NPCs are associated with genetic diseases, but how they manifest only in specific tissues remains unclear. This is exemplified in Nup133-deficient mouse embryonic stem cells, which grow normally during pluripotency, but differentiate poorly into neurons. Here, using an innovative in situ structural biology approach, we show that Nup133 mouse embryonic stem cells have heterogeneous NPCs with non-canonical symmetries and missing subunits. During neuronal differentiation, Nup133-deficient NPCs frequently disintegrate, resulting in abnormally large nuclear envelope openings. We propose that the elasticity of the NPC scaffold has a protective function for the nuclear envelope and that its perturbation becomes critical under conditions that impose an increased mechanical load onto nuclei.
核孔复合体（NPCs）介导核质交换，这对真核生物至关重要。NPCs中央支架成分的突变与遗传疾病相关，但它们如何仅在特定组织中表现尚不清楚。这在缺乏Nup133的小鼠胚胎干细胞中得到了体现，这些细胞在多能性期间正常生长，但向神经元的分化能力较差。在这里，我们使用一种创新的原位结构生物学方法表明，Nup133小鼠胚胎干细胞具有具有非经典对称性和缺失亚基的异质性NPCs。在神经元分化过程中，缺乏Nup133的NPCs经常解体，导致核膜开口异常增大。我们提出，NPC支架的弹性对核膜具有保护作用，并且在对细胞核施加增加的机械负荷的条件下，其扰动变得至关重要。
