Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain.
Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain.
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DOI：
10.1016/j.molcel.2020.10.041
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发表时间：
2020-12-03
期刊：
影响因子：
16
通讯作者：
Youle RJ
中科院分区：
文献类型：
--
作者：
Sarraf SA;Shah HV;Kanfer G;Pickrell AM;Holtzclaw LA;Ward ME;Youle RJ
蛋白质聚集体破坏细胞内稳态，导致与神经退化有关的毒性。聚集体的选择性自噬消除是蛋白质质量控制的关键，但如何选择性地针对聚集体进行降解尚不清楚。我们比较了自噬受体蛋白：OPTN、NBR1、P62、NDP52和TAX1BP1在清除蛋白毒性聚集体方面的需求。内源性TAX1BP1被招募到应激诱导的聚集体的清除中，而TAX1BP1的异位表达通过自噬增加了清除，促进了人类诱导的多能干细胞来源的神经元的活性。相反，TAX1BP1的耗尽使细胞对几种形式的聚集体诱导的蛋白毒性敏感。此外，与其他自噬受体蛋白相比，TAX1BP1在大脑中的表达更具特异性。在体内，TAX1BP1基因缺失会导致幼年TAX1BP1基因敲除小鼠脑内高分子量泛素结合物的积累和脂褐素的过早积累。TAX1BP1介导了一系列细胞毒性蛋白的清除，表明了神经退行性疾病的治疗潜力。Sarraf等人。发现自噬受体TAX1BP1在清除由广泛的蛋白毒性应激诱导的蛋白质聚集中的作用，包括翻译应激、蛋白酶体抑制和Huntingtin蛋白的表达。缺乏功能TAX1BP1的小鼠在大脑中积累泛素化蛋白结合物。
Protein aggregates disrupt cellular homeostasis, causing toxicity linked to neurodegeneration. Selective autophagic elimination of aggregates is critical to protein quality control, but how aggregates are selectively targeted for degradation is unclear. We compared the requirements for autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in clearance of proteotoxic aggregates. Endogenous TAX1BP1 is recruited to and required for the clearance of stress-induced aggregates, whereas ectopic expression of TAX1BP1 increases clearance through autophagy, promoting viability of human induced pluripotent stem cell-derived neurons. In contrast, TAX1BP1 depletion sensitizes cells to several forms of aggregate-induced proteotoxicity. Furthermore, TAX1BP1 is more specifically expressed in the brain compared to other autophagy receptor proteins. In vivo, loss of TAX1BP1 results in accumulation of high molecular weight ubiquitin conjugates and premature lipofuscin accumulation in brains of young TAX1BP1 knockout mice. TAX1BP1 mediates clearance of a broad range of cytotoxic proteins indicating therapeutic potential in neurodegenerative diseases. Sarraf et al. discover a role for the autophagy receptor TAX1BP1 in clearance of protein aggregates induced by a broad range of proteotoxic stresses, including translational stress, proteasome inhibition, and expression of huntingtin protein. Mice lacking functional TAX1BP1 accumulate ubiquitinated protein conjugates in the brain.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
14.8
作者：
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影响因子：
3.3
作者：
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影响因子：
13.3
作者：
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通讯作者：
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影响因子：
64.8
作者：
Khaminets, Aliaksandr;Heinrich, Theresa;Dikic, Ivan
通讯作者：
Dikic, Ivan