Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease
Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease
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DOI：
10.1038/sj.mt.6300163
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发表时间：
2007-06-01
影响因子：
12.4
通讯作者：
Uney, J. B.
中科院分区：
文献类型：
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作者：
Howarth, J. L.;Kelly, S.;Uney, J. B.
我们研究了热休克，DNAJ-like-1(HSJ1)蛋白(包含DNAJ和泛素相互作用基序)减少多谷氨酰胺介导的包涵体形成的能力。实验表明，热休克蛋白70(HSP70)、HSP40、HSJ1a和HSJ1b的表达显著减少了脊髓和延髓肌萎缩症(SBMA)模型中蛋白质包涵体的形成。HSJ1a还介导了蛋白质聚集的初级神经元模型中形成的包涵体数量的显著减少。阐明这些减少的机制的研究表明，HSP70和HSP40增加了伴侣介导的复性。相反，HSJ1蛋白的表达没有促进伴侣活性，但导致泛素化增加。此外，HSJ1a与泛素化的荧光素酶复合体相关，在HSJ1a而不是HSJ1a UIM突变体(HSJ1a-Delta UIM)存在的情况下，荧光素酶蛋白水平降低。综上所述，这些结果表明HSJ1蛋白通过泛素-蛋白酶体系统(UPS)介导了靶蛋白降解的增加。我们还发现，HSJ1a的表达显著减少了体内聚谷氨酰胺病模型中包含包涵体的神经元的数量。这些发现表明，对UPS进行靶向修饰以促进错误折叠蛋白的降解可能是治疗多谷氨酰胺病的一种高效的治疗途径。
We studied the ability of heat shock, DnaJ-like-1 (HSJ1) proteins (which contain DnaJ and ubiquitin-interacting motifs) to reduce polyglutamine-mediated inclusion formation. The experiments demonstrated that expression of heat shock protein 70 (hsp70), hsp40, HSJ1a, and HSJ1b significantly reduced protein inclusion formation in a model of spinal and bulbar muscular atrophy (SBMA). HSJ1a also mediated a significant decrease in the number of inclusions formed in a primary neuronal model of protein aggregation. Studies to elucidate the mechanisms underlying these reductions showed that hsp70 and hsp40 increased chaperone-mediated refolding. In contrast, expression of HSJ1 proteins did not promote chaperone activity but caused an increase in ubiquitylation. Furthermore, HSJ1a was associated with a ubiquitylated luciferase complex, and in the presence of HSJ1a but not an HSJ1a UIM mutant (HSJ1a-Delta UIM) there was a reduction in luciferase protein levels. Together these results show that HSJ1 proteins mediated an increase in target protein degradation via the ubiquitin-proteasome system ( UPS). We also found that the expression of HSJ1a significantly decreased the number of neurons containing inclusions in an in vivo model of polyglutamine disease. These findings indicate that targeted modification of the UPS to facilitate degradation of misfolded proteins may represent a highly effective therapeutic avenue for the treatment of polyglutamine disease.