MAPT/Tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: a vicious cycle in Alzheimer neurodegeneration
MAPT/Tau accumulation represses autophagy flux by disrupting IST1-regulated ESCRT-III complex formation: a vicious cycle in Alzheimer neurodegeneration
复制标题
MAPT/Tau 积累通过破坏 IST1 调节的 ESCRT-III 复合物形成来抑制自噬通量：阿尔茨海默神经变性的恶性循环。
DOI：
10.1080/15548627.2019.1633862
复制
发表时间：
2019-06-29
期刊：
影响因子：
13.3
通讯作者：
Wang, Jian-Zhi
中科院分区：
文献类型：
--
作者：
Feng, Qiong;Luo, Yu;Wang, Jian-Zhi
巨噬/自噬缺陷诱导细胞内MAPT/tau积累，这是阿尔茨海默病（AD）和其他tau病的标志性病理；然而，MAPT积累在自噬和神经退行性变中的反向作用尚不清楚。在本研究中，我们发现人类野生型全长MAPT的过表达（它模拟了散发性AD患者的MAPT病理）通过抑制自噬体-溶酶体融合诱导自噬缺陷，导致LC3（微管相关蛋白1轻链3）-II和SQSTM1/p62（固溶体1）蛋白水平显著升高，自噬体积累。在分子水平上，细胞内MAPT聚集抑制IST1（与ESCRT- iii相关的IST1因子）的表达，IST1是自噬体与溶酶体融合所必需的ESCRT（运输所需的内体分选复合物）复合物形成的正调节因子。在人MAPT转基因小鼠中，上调IST1可减轻自噬缺陷，减少MAPT聚集，改善突触可塑性和认知功能，而在幼稚小鼠中，下调IST1本身可诱导自噬缺陷，损害突触和认知功能。IST1可以促进CHMP2B（带电多泡体蛋白2B）和CHMP4B/SNF7-2结合形成ESCRT-III复合物，而缺乏IST1则会阻碍复合物的形成。最后，我们证明了MAPT积累抑制IST1转录的机制涉及anp32a调节的组蛋白乙酰化掩膜。我们的研究结果表明，AD样的MAPT积累可以通过调节ANP32A-INHAT-IST1-ESCRT-III通路抑制自噬体-溶酶体融合，这也揭示了在AD神经退行性变的慢性过程中MAPT积累和自噬缺陷的恶性循环。
Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in Alzheimer disease (AD) and other tauopathies; however, the reverse role of MAPT accumulation in autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (microtubule-associated protein 1 light chain 3)-II and SQSTM1/p62 (sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with ESCRT-III), a positive modulator for the formation of ESCRT (the Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naive mice. IST1 can facilitate association of CHMP2B (charged multivesicular body protein 2B) and CHMP4B/SNF7-2 to form ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.