Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD 20742, USA.
Mol Cell. 2020 Dec 3;80(5):779-795.e10. doi: 10.1016/j.molcel.2020.10.041. Epub 2020 Nov 17.
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.
蛋白质聚集体破坏细胞内稳态，导致与神经退行性变相关的毒性。选择性自噬消除聚集体对于蛋白质质量控制至关重要，但聚集体如何被选择性靶向降解尚不清楚。我们比较了自噬受体蛋白 OPTN、NBR1、p62、NDP52 和 TAX1BP1 在清除毒性蛋白聚集体方面的需求。内源性 TAX1BP1 被募集并需要用于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，从而促进人诱导多能干细胞源性神经元的存活。相比之下，TAX1BP1 的耗竭使细胞对几种聚集体诱导的毒性敏感。此外，与其他自噬受体蛋白相比，TAX1BP1 在大脑中特异性表达。在体内，TAX1BP1 的缺失导致高分子量泛素缀合物的积累和年轻 TAX1BP1 敲除小鼠大脑中脂褐素的过早积累。TAX1BP1 介导广泛的细胞毒性蛋白的清除，表明在神经退行性疾病中有治疗潜力。
