Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, USA.
Medical Scientist Training Program, University of Virginia, Charlottesville, VA 22903, USA.
Biomolecules. 2023 Sep 16;13(9):1399. doi: 10.3390/biom13091399.
Intracellular endosomal trafficking controls the balance between protein degradation and synthesis, i.e., proteostasis, but also many of the cellular signaling pathways that emanate from activated growth factor receptors after endocytosis. Endosomal trafficking, sorting, and motility are coordinated by the activity of small GTPases, including Rab proteins, whose function as molecular switches direct activity at endosomal membranes through effector proteins. Rab7 is particularly important in the coordination of the degradative functions of the pathway. Rab7 effectors control endosomal maturation and the properties of late endosomal and lysosomal compartments, such as coordination of recycling, motility, and fusion with downstream compartments. The spatiotemporal regulation of endosomal receptor trafficking is particularly challenging in neurons because of their enormous size, their distinct intracellular domains with unique requirements (dendrites vs. axons), and their long lifespans as postmitotic, differentiated cells. In Charcot-Marie-Tooth 2B disease (CMT2B), familial missense mutations in Rab7 cause alterations in GTPase cycling and trafficking, leading to an ulcero-mutilating peripheral neuropathy. The prevailing hypothesis to account for CMT2B pathologies is that CMT2B-associated Rab7 alleles alter endocytic trafficking of the neurotrophin NGF and its receptor TrkA and, thereby, disrupt normal trophic signaling in the peripheral nervous system, but other Rab7-dependent pathways are also impacted. Here, using TrkA as a prototypical endocytic cargo, we review physiologic Rab7 effector interactions and control in neurons. Since neurons are among the largest cells in the body, we place particular emphasis on the temporal and spatial regulation of endosomal sorting and trafficking in neuronal processes. We further discuss the current findings in CMT2B mutant Rab7 models, the impact of mutations on effector interactions or balance, and how this dysregulation may confer disease.
细胞内内体运输控制着蛋白质降解和合成之间的平衡，即蛋白质稳态，但也控制着许多从内吞作用后激活的生长因子受体发出的细胞信号通路。内体运输、分拣和运动是由小 GTPases 的活性协调的，包括 Rab 蛋白，其作为分子开关的功能通过效应蛋白指导内体膜的活性。Rab7 在协调途径的降解功能方面尤为重要。Rab7 效应物控制着内体的成熟以及晚期内体和溶酶体区室的特性，例如协调回收、运动和与下游区室的融合。由于神经元的巨大体积、具有独特需求（树突与轴突）的独特细胞内结构域以及作为有丝分裂后分化细胞的长寿命，内体受体运输的时空调节在神经元中特别具有挑战性。在 Ch arcot-Marie-Tooth 2B 疾病（CMT2B）中，Rab7 的家族性错义突变导致 GTPase循环和运输发生改变，导致溃疡性破坏性周围神经病。解释 CMT2B 病理学的主要假说是 CMT2B 相关 Rab7 等位基因改变了神经营养因子 NGF 及其受体 TrkA 的内吞运输，从而破坏了周围神经系统中的正常营养信号，但其他依赖 Rab7 的途径也受到影响。在这里，我们使用 TrkA 作为典型的内吞货物，综述了神经元中生理 Rab7 效应物相互作用和控制。由于神经元是体内最大的细胞之一，我们特别强调了神经元突起中内体分拣和运输的时空调节。我们进一步讨论了 CMT2B 突变 Rab7 模型中的当前发现、突变对效应物相互作用或平衡的影响，以及这种失调如何导致疾病。
