Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot-Marie-Tooth 2B Disease.
Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot-Marie-Tooth 2B Disease.
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DOI：
10.3390/biom13091399
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发表时间：
2023-09-16
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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作者：
细胞内内体运输控制蛋白质降解和合成之间的平衡，即，这些信号通路不仅与蛋白质稳态有关，而且还与内吞作用后从活化的生长因子受体发出的许多细胞信号通路有关。内体运输、分选和运动性由小GTP酶（包括Rab蛋白）的活性协调，其作为分子开关的功能通过效应蛋白引导内体膜的活性。Rab 7在协调该途径的降解功能中特别重要。Rab 7效应子控制内体成熟和晚期内体和溶酶体隔室的性质，如再循环、运动性和与下游隔室融合的协调。内体受体运输的时空调节在神经元中特别具有挑战性，因为它们的巨大尺寸，它们具有独特要求的独特细胞内结构域（树突与轴突），以及它们作为有丝分裂后分化细胞的长寿命。在Charcot-Marie-Tooth 2B疾病（CMT 2B）中，Rab 7的家族性错义突变导致GTT循环和运输的改变，导致溃疡性周围神经病变。解释CMT 2B病理的流行假设是CMT 2B相关Rab 7等位基因改变神经营养因子NGF及其受体TrkA的内吞运输，从而破坏外周神经系统中的正常营养信号传导，但其他Rab 7依赖性途径也受到影响。在这里，使用TrkA作为一个典型的内吞货物，我们审查生理Rab 7效应器的相互作用和控制神经元。由于神经元是体内最大的细胞之一，我们特别强调的时间和空间调节内体的排序和贩运的神经元过程。我们进一步讨论了CMT 2B突变Rab 7模型的当前发现，突变对效应子相互作用或平衡的影响，以及这种失调如何导致疾病。
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.
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影响因子：
5.7
作者：
da Silva S;Wang F
通讯作者：
Wang F
轴突自噬体通过融合与晚期内体募集动力蛋白进行逆行转运。
DOI：
10.1083/jcb.201412046
发表时间：
2015-05-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cheng XT;Zhou B;Lin MY;Cai Q;Sheng ZH
通讯作者：
Sheng ZH
DOI：
10.1083/jcb.202010179
发表时间：
2021-07-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cason SE;Carman PJ;Van Duyne C;Goldsmith J;Dominguez R;Holzbaur ELF
通讯作者：
Holzbaur ELF
影响因子：
12.7
作者：
Cogli, Laura;Progida, Cinzia;Bucci, Cecilia
通讯作者：
Bucci, Cecilia
影响因子：
3.9
作者：
Cogli, Laura;Piro, Francesco;Bucci, Cecilia
通讯作者：
Bucci, Cecilia