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Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain
Molecular Cell ( IF 14.5 ) Pub Date : 2020-11-17 , DOI: 10.1016/j.molcel.2020.10.041
Shireen A Sarraf 1 , Hetal V Shah 2 , Gil Kanfer 1 , Alicia M Pickrell 3 , Lynne A Holtzclaw 4 , Michael E Ward 1 , Richard J Youle 2
Affiliation  

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.



中文翻译:

TAX1BP1 定向自噬的丧失导致大脑中蛋白质聚集体的积累

蛋白质聚集体破坏细胞稳态,导致与神经退行性变相关的毒性。聚集体的选择性自噬消除对蛋白质质量控​​制至关重要,但如何选择性地靶向降解聚集体尚不清楚。我们比较了自噬受体蛋白的要求:OPTN、NBR1、p62、NDP52 和 TAX1BP1 在清除蛋白毒性聚集体方面的要求。内源性 TAX1BP1 被募集到并需要清除应激诱导的聚集体,而 TAX1BP1 的异位表达通过自噬增加清除,促进人类诱导的多能干细胞衍生神经元的活力。相比之下,TAX1BP1 消耗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 在大脑中的表达更为特异。在体内,TAX1BP1 的缺失导致年轻 TAX1BP1 敲除小鼠大脑中高分子量泛素缀合物的积累和过早的脂褐质积累。TAX1BP1 介导多种细胞毒性蛋白的清除,表明在神经退行性疾病中的治疗潜力。

更新日期:2020-12-03
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