Successful regeneration of severed peripheral nerves requires the breakdown and subsequent clearance of myelin, tightly packed membrane sheaths of Schwann cells that protect nerve fibers and harbor nerve growth-inhibitory proteins. How Schwann cells initiate myelin breakdown in response to injury is still largely unknown. Here we report that, following sciatic nerve injury, MLKL, a pseudokinase known to rupture cell membranes during necroptotic cell death, is induced and targets the myelin sheath membrane of Schwann cells to promote myelin breakdown. The function of MLKL in disrupting myelin sheaths requires injury-induced phosphorylation of serine 441, an activation signal distinct from the necroptosis-inducing phosphorylation by RIP3 kinase. Mice with Mlkl specifically knocked out in Schwann cells showed delayed myelin sheath breakdown. Lack of MLKL reduced nerve regeneration following injury, whereas overexpression of MLKL accelerated myelin breakdown and promoted the regeneration of axons.

切断的周围神经的成功再生需要髓磷脂，雪旺氏细胞紧密堆积的膜鞘的破裂和随后的清除，保护神经纤维并保留神经生长抑制蛋白。雪旺细胞如何响应损伤而引发髓磷脂分解仍然是未知的。在这里，我们报告说，坐骨神经损伤后，MLKL是一种已知的假激酶，已知其会在坏死性细胞死亡期间破坏细胞膜，并靶向施旺细胞的髓鞘膜，以促进髓鞘分解。MLKL在破坏髓鞘中的功能需要丝氨酸441的损伤诱导的磷酸化，该活化信号不同于通过RIP3激酶的坏死病诱导的磷酸化。Mlkl的小鼠特别是在雪旺氏细胞中被剔除，显示出髓鞘鞘的延迟分解。缺乏MLKL会减少损伤后的神经再生，而MLKL的过表达会加速髓磷脂的分解并促进轴突的再生。