Filamin A Is Required in Injured Axons for HDAC5 Activity and Axon Regeneration
Filamin A Is Required in Injured Axons for HDAC5 Activity and Axon Regeneration
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DOI：
10.1074/jbc.m115.638445
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发表时间：
2015-09-11
影响因子：
4.8
通讯作者：
Cavalli, Valeria
中科院分区：
文献类型：
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作者：
Cho, Yongcheol;Park, Dongeun;Cavalli, Valeria
微管动力学对于发育过程中的轴突生长以及损伤后的轴突再生很重要。我们之前已经鉴定出 HDAC5 是一种损伤调节的微管蛋白脱乙酰酶，在损伤部位发挥作用，促进轴突再生。然而，HDAC5 活性空间控制所涉及的机制仍然知之甚少。在这里，我们揭示了 HDAC5 通过其 C 端结构域与肌动蛋白结合蛋白 filamin A 相互作用。细丝蛋白 A 在 HDAC5 依赖性微管蛋白脱乙酰化中发挥关键作用，因为在缺乏细丝蛋白 A 的细胞中，乙酰化微管蛋白的水平显着升高。我们发现神经损伤以蛋白质合成依赖性方式增加细丝蛋白 A 轴突表达。降低细丝蛋白 A 水平或干扰 HDAC5 与细丝蛋白 A 之间的相互作用可防止损伤诱导的微管蛋白脱乙酰化以及 HDAC5 在受损轴突尖端的定位。此外，缺乏细丝蛋白 A 的神经元表现出轴突再生减少。我们的研究结果提出了一个模型，其中轴突损伤后的细丝蛋白 A 局部翻译控制局部 HDAC5 活性以促进轴突再生。
Microtubule dynamics are important for axon growth during development as well as axon regeneration after injury. We have previously identified HDAC5 as an injury-regulated tubulin deacetylase that functions at the injury site to promote axon regeneration. However, the mechanisms involved in the spatial control of HDAC5 activity remain poorly understood. Here we reveal that HDAC5 interacts with the actin binding protein filamin A via its C-terminal domain. Filamin A plays critical roles in HDAC5-dependent tubulin deacetylation because, in cells lacking filamin A, the levels of acetylated tubulin are elevated markedly. We found that nerve injury increases filamin A axonal expression in a protein synthesis-dependent manner. Reducing filamin A levels or interfering with the interaction between HDAC5 and filamin A prevents injury-induced tubulin deacetylation as well as HDAC5 localization at the injured axon tips. In addition, neurons lacking filamin A display reduced axon regeneration. Our findings suggest a model in which filamin A local translation following axon injury controls localized HDAC5 activity to promote axon regeneration.