IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome.
IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome.
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DOI：
10.1083/jcb.200909067
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发表时间：
2009-12-28
期刊：
影响因子：
--
通讯作者：
Steffan JS
中科院分区：
文献类型：
--
作者：
Thompson LM;Aiken CT;Kaltenbach LS;Agrawal N;Illes K;Khoshnan A;Martinez-Vincente M;Arrasate M;O'Rourke JG;Khashwji H;Lukacsovich T;Zhu YZ;Lau AL;Massey A;Hayden MR;Zeitlin SO;Finkbeiner S;Green KN;LaFerla FM;Bates G;Huang L;Patterson PH;Lo DC;Cuervo AM;Marsh JL;Steffan JS
在亨廷顿病中突变的蛋白质被炎性激酶IKK磷酸化，其促进其他翻译后修饰和蛋白质降解。亨廷顿蛋白（Htt）内多聚谷氨酰胺重复序列的扩增导致亨廷顿病，这是一种与衰老和突变型Htt在患病神经元中积累相关的神经变性疾病。了解影响Htt细胞降解的机制可能会针对旨在激活突变型Htt清除途径的治疗。我们发现Htt被炎症激酶IKK磷酸化，增强了蛋白酶体和溶酶体对其的正常清除。Htt的磷酸化调节额外的翻译后修饰，包括Htt泛素化、SUMO化和乙酰化，并增加由溶酶体相关膜蛋白2A和Hsc 70介导的Htt核定位、切割和清除。我们建议IKK激活突变体Htt清除，直到与年龄相关的蛋白酶体/溶酶体功能丧失促进有毒的后消化修饰的突变体Htt的积累。因此，IKK激活可以调节突变体Htt神经毒性，这取决于细胞降解修饰物种的能力。
The protein mutated in Huntington's disease is phosphorylated by the inflammatory kinase IKK, which promotes other post-translational modifications, and protein degradation. Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species.
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