Abstract：
Schwann cells play critical roles in peripheral neuropathies; however, the regulatory mechanisms of their homeostasis remain largely unknown. Here, we show that nucleoporin Seh1, a component of nuclear pore complex, is important for Schwann cell homeostasis. Expression of Seh1 decreases as mice age. Loss of Seh1 leads to activated immune responses and cell necroptosis. Mice with depletion of Seh1 in Schwann cell lineage develop progressive reduction of Schwann cells in sciatic nerves, predominantly non-myelinating Schwann cells, followed by neural fiber degeneration and malfunction of the sensory and motor system. Mechanistically, Seh1 safeguards genome stability by mediating the interaction between SETDB1 and KAP1. The disrupted interaction after ablation of Seh1 derepresses endogenous retroviruses, which triggers ZBP1-dependent necroptosis in Schwann cells. Collectively, our results demonstrate that Seh1 is required for Schwann cell homeostasis by maintaining genome integrity and suggest that decrease of nucleoporins may participate in the pathogenesis of periphery neuropathies.
摘要：
雪旺氏细胞在周围神经病变中起关键作用；然而，其稳态的调节机制在很大程度上仍然未知。这里,我们表明核孔蛋白Seh1是核孔复合物的一个组成部分，对雪旺氏细胞稳态很重要。Seh1的表达随着小鼠年龄的增长而降低。Seh1的缺失导致激活的免疫应答和细胞坏死。Schwann细胞系中Seh1耗竭的小鼠在坐骨神经中逐渐减少Schwann细胞，主要是非髓鞘化雪旺氏细胞，其次是神经纤维变性和感觉和运动系统故障。机械上,Seh1通过介导SETDB1和KAP1之间的相互作用来保护基因组稳定性。Seh1消融后破坏的相互作用抑制了内源性逆转录病毒，在施万细胞中触发ZBP1依赖性坏死。总的来说，我们的结果表明，Seh1通过维持基因组完整性而成为施万细胞稳态所必需的，并提示核孔蛋白的减少可能参与周围神经病变的发病机制。
