Hsp70- and Hsp90-mediated proteasomal degradation underlies TPIsugarkill pathogenesis in Drosophila
Hsp70- and Hsp90-mediated proteasomal degradation underlies TPIsugarkill pathogenesis in Drosophila
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DOI：
10.1016/j.nbd.2010.08.011
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发表时间：
2010-12-01
影响因子：
6.1
通讯作者：
Palladino, Michael J.
中科院分区：
文献类型：
--
作者：
Hrizo, Stacy L.;Palladino, Michael J.
磷酸丙糖异构酶（TPI）缺乏症是一种严重的糖酵解酶病，可导致进行性运动障碍和神经退行性变、感染易感性和过早死亡。黑腹果蝇隐性错义TPI sugarkill突变表现出与人类TPI缺乏症类似的表型，如进行性运动障碍、神经变性和寿命缩短。我们已经表明，TPIsugarkill蛋白是一种活性稳定的二聚体;然而，突变蛋白被蛋白酶体转化，降低了这种糖酵解酶的细胞水平。由于蛋白酶体功能通常与分子伴侣活性相结合，因此我们假设TPI sugarkill被介导突变蛋白的蛋白酶体降解的分子伴侣所识别。免疫共沉淀数据和分析的TPIsugarkill营业额在动物减少或增强分子伴侣活性表明，热休克蛋白90和热休克蛋白70是重要的目标TPIsugarkill降解。此外，通过药理学或遗传操作修饰的分子伴侣和蛋白酶体活性导致TPI糖杀伤蛋白水平提高，并挽救了部分但非全部疾病表型，表明TPI缺乏症病理学复杂。总体而言，这些数据证明了Hsp 70和Hsp 90在TPI缺乏相关神经功能障碍进展中的惊人作用。(C)2010年爱思唯尔公司All rights reserved.
Triosephosphate isomerase (TPI) deficiency is a severe glycolytic enzymopathy that causes progressive locomotor impairment and neurodegeneration, susceptibility to infection, and premature death. The recessive missense TPIsugarkill mutation in Drosophila melanogaster exhibits phenotypes analogous to human TPI deficiency such as progressive locomotor impairment, neurodegeneration, and reduced life span. We have shown that the TPIsugarkill protein is an active stable dimer; however, the mutant protein is turned over by the proteasome reducing cellular levels of this glycolytic enzyme.. As proteasome function is often coupled with molecular chaperone activity, we hypothesized that TPIsugarkill is recognized by molecular chaperones that mediate the proteasomal degradation of the mutant protein. Coimmunoprecipitation data and analyses of TPIsugarkill turnover in animals with reduced or enhanced molecular chaperone activity indicate that both Hsp90 and Hsp70 are important for targeting TPIsugarkill for degradation. Furthermore, molecular chaperone and proteasome activity modified by pharmacological or genetic manipulations resulted in improved TPIsugarkill protein levels and rescue some but not all of the disease phenotypes suggesting that TPI deficiency pathology is complex. Overall, these data demonstrate a surprising role for Hsp70 and Hsp90 in the progression of neural dysfunction associated with TPI deficiency. (C) 2010 Elsevier Inc. All rights reserved.