State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Department of Gynaecology and Obstetrics, Women and Children's Hospital Affiliated to Xiamen University, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Department of Clinic Laboratory, the affiliated Chenggong Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
Cell Rep. 2023 Jul 25;42(7):112802. doi: 10.1016/j.celrep.2023.112802. Epub 2023 Jul 14.
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.
许旺细胞在周围神经病变中发挥关键作用；然而，其维持内稳态的调控机制在很大程度上仍不清楚。在这里，我们表明核孔复合体的组成部分核孔蛋白 Seh1 对于许旺细胞的内稳态很重要。随着小鼠年龄的增长，Seh1 的表达减少。Seh1 的缺失会导致免疫反应的激活和细胞坏死性凋亡。在许旺细胞谱系中耗尽 Seh1 的小鼠，坐骨神经中的许旺细胞逐渐减少，主要是非髓鞘形成的许旺细胞，随后神经纤维退化，感觉和运动系统功能障碍。从机制上讲，Seh1 通过介导 SETDB1 和 KAP1 之间的相互作用来保护基因组的稳定性。Seh1 缺失后，这种相互作用被打乱，内源性逆转录病毒被解除抑制，这会触发许旺细胞中 ZBP1 依赖性坏死性凋亡。总的来说，我们的结果表明，Seh1 通过维持基因组完整性来维持许旺细胞的内稳态，并表明核孔蛋白的减少可能参与周围神经病变的发病机制。
