Nucleoporin Seh1 maintains Schwann cell homeostasis by regulating genome stability and necroptosis

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. [Display omitted] •Seh1 is essential for Schwann cell homeostasis and peripheral sensory function•Loss of Seh1 activates necroptosis in a ZBP1-dependent manner•Seh1 represses ERV expression by mediating the interaction between SETDB1 and KAP1•Reverse transcriptase inhibitor alleviates the abnormality in periphery nerves Wu et al. demonstrate that nucleoporin Seh1 is essential for Schwann cell homeostasis and peripheral sensory function. They find that loss of Seh1 derepresses ERV production and activates necroptosis in Schwann cells, which can be rescued by reverse transcriptase inhibitors.