Tau can switch microtubule network organizations: from random networks to dynamic and stable bundles.
Tau can switch microtubule network organizations: from random networks to dynamic and stable bundles.
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DOI：
10.1091/mbc.e17-06-0429
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发表时间：
2018-01-15
影响因子：
3.3
通讯作者：
Arnal I
中科院分区：
文献类型：
--
作者：
Prezel E;Elie A;Delaroche J;Stoppin-Mellet V;Bosc C;Serre L;Fourest-Lieuvin A;Andrieux A;Vantard M;Arnal I
Tau是一种神经元微管稳定剂，已知其通过促进微管的生长和抑制其收缩来稳定微管。这项研究揭示了新的机制，tau蛋白能够通过微管捆绑和动力学的差异调节来切换微管网络组织。在神经元中，微管网络在控制其动力学和组织的效应器的影响下在单丝和成束阵列之间交替。Tau是一种微管稳定剂，通过刺激生长和抑制收缩来稳定微管。tau组织微管网络的机制仍然知之甚少。在这里，我们研究了在tau亚型和突变体存在下生长的微管的自组织。结果表明，tau蛋白诱导稳定的微管束的能力需要两个六肽位于其微管结合域，并通过其投影域调制。tau蛋白的位点特异性假磷酸化促进不同的微管组织：稳定的单个微管，稳定的束或动态束。疾病相关的tau突变增加了高度动态束的形成。最后，低温电子显微镜实验表明，tau蛋白及其变体通过增加原丝数量和晶格缺陷来类似地改变微管晶格结构。总的来说，我们的研究结果揭示了控制tau触发微管组织能力的新的磷酸依赖性机制，并揭示了tau的疾病相关修饰促进了特定的微管组织，这些微管组织可能在神经退行性变期间产生有害影响。
Tau is a neuronal microtubule bundler that is known to stabilize microtubules by promoting their growth and inhibiting their shrinkage. This study reveals novel mechanisms by which tau is able to switch microtubule network organizations via the differential regulation of microtubule bundling and dynamics. In neurons, microtubule networks alternate between single filaments and bundled arrays under the influence of effectors controlling their dynamics and organization. Tau is a microtubule bundler that stabilizes microtubules by stimulating growth and inhibiting shrinkage. The mechanisms by which tau organizes microtubule networks remain poorly understood. Here, we studied the self-organization of microtubules growing in the presence of tau isoforms and mutants. The results show that tau’s ability to induce stable microtubule bundles requires two hexapeptides located in its microtubule-binding domain and is modulated by its projection domain. Site-specific pseudophosphorylation of tau promotes distinct microtubule organizations: stable single microtubules, stable bundles, or dynamic bundles. Disease-related tau mutations increase the formation of highly dynamic bundles. Finally, cryo–electron microscopy experiments indicate that tau and its variants similarly change the microtubule lattice structure by increasing both the protofilament number and lattice defects. Overall, our results uncover novel phosphodependent mechanisms governing tau’s ability to trigger microtubule organization and reveal that disease-related modifications of tau promote specific microtubule organizations that may have a deleterious impact during neurodegeneration.