N-alpha-acetylation of Huntingtin protein increases its propensity to aggregate.
N-alpha-acetylation of Huntingtin protein increases its propensity to aggregate.
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DOI：
10.1016/j.jbc.2021.101363
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Marmorstein R
中科院分区：
文献类型：
--
作者：
Gottlieb L;Guo L;Shorter J;Marmorstein R
亨廷顿病（HD）是由HTT基因第一外显子中的多聚CAG扩增引起的神经退行性疾病，导致亨廷顿蛋白（Htt）产物的N-末端结构域中的多聚谷氨酰胺束延伸。含有多聚谷氨酰胺的N-末端结构域的蛋白水解片段形成与HD相关的核内聚集体。已显示Htt的翻译后修饰改变其功能和聚集性质。然而，尚未考虑N-末端Htt乙酰化的影响。在这里，我们开发了一种细菌系统，以产生未修饰的或N-末端乙酰化和聚集诱导的Htt蛋白。我们使用这个系统与生物化学，生物物理，和成像研究，以确认Htt N-末端是在体外底物的NatA N-末端乙酰转移酶，并显示N-末端乙酰化促进聚集。这些研究代表了N-末端乙酰化和促进神经退行性疾病之间的第一个联系，并暗示NatA介导的Htt乙酰化是HD中新的潜在治疗靶点。
Huntington’s disease (HD) is a neurodegenerative disorder caused by a poly-CAG expansion in the first exon of the HTT gene, resulting in an extended poly-glutamine tract in the N-terminal domain of the Huntingtin (Htt) protein product. Proteolytic fragments of the poly-glutamine–containing N-terminal domain form intranuclear aggregates that are correlated with HD. Post-translational modification of Htt has been shown to alter its function and aggregation properties. However, the effect of N-terminal Htt acetylation has not yet been considered. Here, we developed a bacterial system to produce unmodified or N-terminally acetylated and aggregation-inducible Htt protein. We used this system together with biochemical, biophysical, and imaging studies to confirm that the Htt N-terminus is an in vitro substrate for the NatA N-terminal acetyltransferase and show that N-terminal acetylation promotes aggregation. These studies represent the first link between N-terminal acetylation and the promotion of a neurodegenerative disease and implicates NatA-mediated Htt acetylation as a new potential therapeutic target in HD.
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影响因子：
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