PDF(Pubmed)
Abstract：
Nucleoporins, the components of nuclear pore complexes (NPCs), can play cell type- and tissue-specific functions. Yet, the physiological roles and mechanisms of action for most NPC components have not yet been established. We report that Nup358, a nucleoporin linked to several myeloid disorders, is required for the developmental progression of early myeloid progenitors. We found that Nup358 ablation in mice results in the loss of myeloid-committed progenitors and mature myeloid cells and the accumulation of myeloid-primed multipotent progenitors (MPPs) in bone marrow. Accumulated MPPs in Nup358 knockout mice are greatly restricted to megakaryocyte/erythrocyte-biased MPP2, which fail to progress into committed myeloid progenitors. Mechanistically, we found that Nup358 is required for histone deacetylase 3 (HDAC3) nuclear import and function in MPP2 cells and established that this nucleoporin regulates HDAC3 nuclear translocation in a SUMOylation-independent manner. Our study identifies a critical function for Nup358 in myeloid-primed MPP2 differentiation and uncovers an unexpected role for NPCs in the early steps of myelopoiesis.
摘要：
核孔蛋白,核孔复合物(NPC)的成分，可以发挥细胞类型和组织特异性功能。然而，大多数NPC成分的生理作用和作用机制尚未确定。我们报道了Nup358，一种与几种髓系疾病有关的核孔蛋白，是早期骨髓祖细胞发育进展所必需的。我们发现，小鼠中的Nup358消融会导致骨髓定向祖细胞和成熟骨髓细胞的丢失，以及骨髓中多能祖细胞（MPPs）的积累。Nup358敲除小鼠中积累的MPP被大大限制于巨核细胞/红细胞偏向性MPP2,其不能进展为定型的骨髓祖细胞。机械上,我们发现Nup358是MPP2细胞中组蛋白脱乙酰酶3（HDAC3）核导入和功能所必需的，并确定了这种核孔蛋白以不依赖SUMO化的方式调节HDAC3核易位。我们的研究确定了Nup358在骨髓引发的MPP2分化中的关键功能，并揭示了NPC在骨髓生成早期步骤中的意外作用。
