Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast.
Neurodegenerative disease-associated inclusion bodies are cleared by selective autophagy in budding yeast.
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DOI：
10.1080/27694127.2023.2236407
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发表时间：
2023-08
期刊：
影响因子：
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通讯作者：
Austin Folger;Chuan Chen;M. Kabbaj;Karina Frey;Yanchang Wang
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文献类型：
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作者：
Austin Folger;Chuan Chen;M. Kabbaj;Karina Frey;Yanchang Wang
蛋白质错误折叠、聚集和积累导致神经退行性疾病。一种这样的疾病，亨廷顿氏病，是由亨廷顿蛋白（HTT）基因第一外显子中编码谷氨酰胺的三核苷酸重复CAG数量增加引起的。多聚谷氨酰胺扩增的Htt外显子1突变蛋白在神经元中易于聚集并形成病理性包涵体。大量的研究表明，错误折叠的蛋白质被泛素-蛋白酶体系统或自噬清除，以减轻其细胞毒性。错误折叠的蛋白质可以形成小的可溶性聚集体或大的不溶性包涵体。先前的工作已经阐明了自噬在错误折叠的蛋白质聚集体的清除中的作用，但是包涵体的自噬清除仍然没有得到很好的表征。在这里，我们使用突变的Htt外显子1与103聚谷氨酰胺（Htt 103 QP）作为模型底物，研究自噬清除包涵体在芽殖酵母。我们发现核心自噬相关蛋白是Htt 103 QP包涵体自噬所必需的。此外，我们的证据表明，Htt 103 QP包涵体的自噬是选择性的。有趣的是，Cue 5/Tollip，一个已知的自噬受体的聚集，是这种包涵体自噬。从芽殖酵母中已知的选择性自噬受体中，我们确定了三个对包涵体自噬至关重要的受体。淀粉样β肽（Aβ42）是阿尔茨海默病大脑中发现的淀粉样斑块的主要成分。有趣的是，类似的选择性自噬途径有助于芽殖酵母中Aβ42包涵体的清除。因此，我们的研究结果揭示了一种新的自噬途径特异性包涵体与神经退行性疾病，我们称之为IBophagy。
Protein misfolding, aggregation, and accumulation cause neurodegenerative disorders. One such disorder, Huntington's disease, is caused by an increased number of glutamine-encoding trinucleotide repeats CAG in the first exon of the huntingtin (HTT) gene. Mutant proteins of Htt exon 1 with polyglutamine expansion are prone to aggregation and form pathological inclusion bodies in neurons. Extensive studies have shown that misfolded proteins are cleared by the ubiquitin-proteasome system or autophagy to alleviate their cytotoxicity. Misfolded proteins can form small soluble aggregates or large insoluble inclusion bodies. Previous works have elucidated the role of autophagy in the clearance of misfolded protein aggregates, but autophagic clearance of inclusion bodies remains poorly characterized. Here we use mutant Htt exon 1 with 103 polyglutamine (Htt103QP) as a model substrate to study the autophagic clearance of inclusion bodies in budding yeast. We found that the core autophagy-related proteins were required for Htt103QP inclusion body autophagy. Moreover, our evidence indicates that the autophagy of Htt103QP inclusion bodies is selective. Interestingly, Cue5/Tollip, a known autophagy receptor for aggrephagy, is dispensable for this inclusion body autophagy. From the known selective autophagy receptors in budding yeast, we identified three that are essential for inclusion body autophagy. Amyloid beta peptide (Aβ42) is a major component of amyloid plaques found in Alzheimer's disease brains. Interestingly, a similar selective autophagy pathway contributes to the clearance of Aβ42 inclusion bodies in budding yeast. Therefore, our results reveal a novel autophagic pathway specific for inclusion bodies associated with neurodegenerative diseases, which we have termed IBophagy.