National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
School of Life Sciences, Tsinghua University, Beijing 100084, China.
Mol Cell. 2018 Nov 1;72(3):457-468.e5. doi: 10.1016/j.molcel.2018.09.011. Epub 2018 Oct 18.
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.
成功的周围神经切断后再生需要髓鞘的分解和随后的清除，髓鞘是施万细胞的紧密包裹的膜鞘，保护神经纤维并含有神经生长抑制蛋白。施万细胞如何响应损伤启动髓鞘分解在很大程度上仍然未知。在这里，我们报告说，在坐骨神经损伤后，MLKL，一种在坏死性细胞死亡过程中已知破坏细胞膜的假激酶，被诱导并靶向施万细胞的髓鞘膜，以促进髓鞘分解。MLKL 在破坏髓鞘中的功能需要损伤诱导的丝氨酸 441 的磷酸化，这是一种与由 RIP3 激酶诱导的坏死性细胞死亡的磷酸化不同的激活信号。在施万细胞中特异性敲除 Mlkl 的小鼠表现出髓鞘分解的延迟。缺乏 MLKL 减少了损伤后的神经再生，而 MLKL 的过表达加速了髓鞘的分解，并促进了轴突的再生。
