Non-enzymatic Activity of the α-Tubulin Acetyltransferase αTAT Limits Synaptic Bouton Growth in Neurons
Non-enzymatic Activity of the α-Tubulin Acetyltransferase αTAT Limits Synaptic Bouton Growth in Neurons
复制标题
DOI：
10.1016/j.cub.2019.12.022
复制
发表时间：
2020-02-24
期刊：
影响因子：
9.2
通讯作者：
Gardner, Melissa K.
中科院分区：
文献类型：
--
作者：
Coombes, Courtney E.;Saunders, Harriet A. J.;Gardner, Melissa K.
神经元轴突终止于突触终扣，与其靶点形成稳定而可塑的连接。突触终扣的发育依赖于一个长期和动态的微管网络，为终扣提供结构稳定性，同时也允许它们的生长和重塑。然而，解释神经元如何适当平衡这两种微管群体的分子尺度机制仍然是一个谜。我们假设，α-微管蛋白乙酰转移酶（α达特），这两个稳定长寿微管对机械应力通过乙酰化，并已涉及促进微管动力学，可以在这一过程中发挥作用。以果蝇神经肌肉接头为模型，我们发现非酶促的d α达特活性通过影响动态而非稳定的微管限制了突触终扣的生长。d α达特的缺失导致异位终结的形成。这些异位终结可以通过重新提供酶失活的d α达特或通过用低浓度的微管靶向剂长春碱（其作用是抑制微管动力学）治疗来类似地抑制。生物物理重建实验表明，非酶促α TAT 1活性使动态微管不稳定，但基本上不影响长寿命微管的稳定性。此外，在微管生长过程中，非酶促α TAT 1活性导致尖端结构越来越长，这与随着微管年龄的增长，突变频率的加速率增加一致，可能是通过尖端结构重塑。通过这些机制，α达特以动态微管为代价富集稳定的微管。我们建议，非酶促α达特活性的动态微管的特异性抑制调节突触终扣发育过程中微管网络的重塑。
Neuronal axons terminate as synaptic boutons that form stable yet plastic connections with their targets. Synaptic bouton development relies on an underlying network of both long-lived and dynamic microtubules that provide structural stability for the boutons while also allowing for their growth and remodeling. However, a molecular-scale mechanism that explains how neurons appropriately balance these two microtubule populations remains a mystery. We hypothesized that alpha-tubulin acetyltransferase (alpha TAT), which both stabilizes long-lived microtubules against mechanical stress via acetylation and has been implicated in promoting microtubule dynamics, could play a role in this process. Using the Drosophila neuromuscular junction as a model, we found that non-enzymatic d alpha TAT activity limits the growth of synaptic boutons by affecting dynamic, but not stable, microtubules. Loss of d alpha TAT results in the formation of ectopic boutons. These ectopic boutons can be similarly suppressed by resupplying enzyme-inactive d alpha TAT or by treatment with a low concentration of the microtubule-targeting agent vinblastine, which acts to suppress microtubule dynamics. Biophysical reconstitution experiments revealed that non-enzymatic alpha TAT1 activity destabilizes dynamic microtubules but does not substantially impact the stability of long-lived microtubules. Further, during microtubule growth, non-enzymatic alpha TAT1 activity results in increasingly extended tip structures, consistent with an increased rate of acceleration of catastrophe frequency with microtubule age, perhaps via tip structure remodeling. Through these mechanisms, alpha TAT enriches for stable microtubules at the expense of dynamic ones. We propose that the specific suppression of dynamic microtubules by non-enzymatic alpha TAT activity regulates the remodeling of microtubule networks during synaptic bouton development.