The nucleoporin gp210/Nup210 controls muscle differentiation by regulating nuclear envelope/ER homeostasis
The nucleoporin gp210/Nup210 controls muscle differentiation by regulating nuclear envelope/ER homeostasis
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DOI：
10.1083/jcb.201410047
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发表时间：
2015-03-16
影响因子：
7.8
通讯作者：
Hetzer, Martin W.
中科院分区：
文献类型：
--
作者：
Gomez-Cavazos, J. Sebastian;Hetzer, Martin W.
以前，我们确定了核孔蛋白gp 210/Nup 210作为肌肉和神经元分化的关键调节因子，但这种核孔蛋白如何发挥其功能以及它是否调节核孔复合物（NPC）活性仍然未知。在这里，我们表明，gp 210/Nup 210介导肌细胞分化在体外通过其保守的N-末端结构域延伸到核周空间。去除C-末端结构域，其部分地使gp 210/Nup 210远离NPC，有效地挽救了由内源性gp 210/Nup 210的敲低引起的分化缺陷。出乎意料的是，缺乏NPC靶向跨膜和C-末端结构域的gp 210/Nup 210突变体足以用于C2 C12成肌细胞分化。我们证明，内质网（ER）应力特异性胱天蛋白酶级联反应在Nup 210耗竭过程中加剧，阻断ER应力介导的细胞凋亡挽救了Nup 210缺陷细胞的分化。我们的研究结果表明，gp 210/Nup 210在细胞分化中的作用是由其大管腔域介导的，它可以独立于NPC协会发挥作用，似乎在维持核膜/ER稳态中发挥关键作用。
Previously, we identified the nucleoporin gp210/Nup210 as a critical regulator of muscle and neuronal differentiation, but how this nucleoporin exerts its function and whether it modulates nuclear pore complex (NPC) activity remain unknown. Here, we show that gp210/Nup210 mediates muscle cell differentiation in vitro via its conserved N-terminal domain that extends into the perinuclear space. Removal of the C-terminal domain, which partially mislocalizes gp210/Nup210 away from NPCs, efficiently rescues the differentiation defect caused by the knockdown of endogenous gp210/Nup210. Unexpectedly, a gp210/Nup210 mutant lacking the NPC-targeting transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. We demonstrate that the endoplasmic reticulum (ER) stress-specific caspase cascade is exacerbated during Nup210 depletion and that blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells. Our results suggest that the role of gp210/Nup210 in cell differentiation is mediated by its large luminal domain, which can act independently of NPC association and appears to play a pivotal role in the maintenance of nuclear envelope/ER homeostasis.