Friedman Meyer J, Li Shihua, Li Xiao-Jiang
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093.
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322.
J Biol Chem. 2009 Oct 9;284(41):27944-27951. doi: 10.1074/jbc.M109.037937. Epub 2009 Aug 5.
Heat shock proteins are up-regulated as a physiological response to stressful stimuli and generally function as molecular chaperones for improperly folded protein substrates. The small heat shock protein HSP27 (or HSPB1) has multiple cytoplasmic roles. HSP27 also can translocate to the nucleus in response to stress, but the functional significance of this nuclear distribution has not been elucidated. We have previously implicated HSP27 as a genetic modifier of spinocerebellar ataxia 17 (SCA17), a neurological disease caused by a polyglutamine expansion in the TATA-binding protein (TBP). Altered expression of HSP27 is also found in cell models of other polyglutamine diseases, including Huntington disease as well as SCA3 and SCA7. Here, we show that Hsp27, unlike Hsp70, is not detected in mutant TBP aggregates in primary cerebellar granule neurons from transgenic SCA17 mice. Although HSP27 overexpression does not reduce the aggregation of cotransfected mutant TBP containing 105 glutamines, it potentiates activated transcription from both TATA-containing and TATA-lacking promoters. Neither HSP40 nor HSP70 elicits the same transcriptional effect. Moreover, HSP27 interacts with the transcription factor SP1, and coexpression of SP1 and nuclear localization signal-tagged HSP27 synergistically activates reporter constructs for the SP1-responsive neurotrophic receptor genes Ngfr(p75) and TRKA. Overexpression of nuclear localization signal-tagged HSP27 also rescues mutant TBP-mediated down-regulation of TrkA in a PC12 cell model of SCA17. These results indicate that nuclear HSP27 can modulate SP1-dependent transcriptional activity to promote neuronal protection.
热休克蛋白作为对压力刺激的生理反应而被上调，通常作为错误折叠蛋白底物的分子伴侣发挥作用。小热休克蛋白HSP27（或HSPB1）具有多种细胞质功能。HSP27也可在应激反应中转位至细胞核，但这种核分布的功能意义尚未阐明。我们之前已表明HSP27是脊髓小脑共济失调17型（SCA17）的遗传修饰因子，SCA17是一种由TATA结合蛋白（TBP）中多聚谷氨酰胺扩增引起的神经疾病。在其他多聚谷氨酰胺疾病的细胞模型中也发现了HSP27表达的改变，包括亨廷顿病以及SCA3和SCA7。在此，我们发现，与Hsp70不同，在转基因SCA17小鼠的原代小脑颗粒神经元的突变TBP聚集体中未检测到Hsp27。虽然HSP27过表达不会减少共转染的含105个谷氨酰胺的突变TBP的聚集，但它能增强来自含TATA和不含TATA启动子的激活转录。HSP40和HSP70均未引发相同的转录效应。此外，HSP27与转录因子SP1相互作用，SP1与核定位信号标记的HSP27共表达可协同激活SP1反应性神经营养受体基因Ngfr(p75)和TRKA的报告构建体。在SCA17的PC12细胞模型中，核定位信号标记的HSP27过表达也能挽救突变TBP介导的TrkA下调。这些结果表明，核HSP27可调节SP1依赖的转录活性以促进神经元保护。
