skn-1-Dependent and -Independent Regulation of aip-1 Expression following Metabolic Stress in Caenorhabditis elegans
skn-1-Dependent and -Independent Regulation of aip-1 Expression following Metabolic Stress in Caenorhabditis elegans
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DOI：
10.1128/mcb.01340-09
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发表时间：
2010-06-01
影响因子：
5.3
通讯作者：
Fisher, Alfred L.
中科院分区：
文献类型：
--
作者：
Ferguson, Annabel A.;Springer, Mitchell G.;Fisher, Alfred L.
面对多种内部和外部应力，稳定，正确折叠和催化活性蛋白质组是对生物体的主要挑战，这些内部应力会损害蛋白质，并导致蛋白质错误折叠。在这里，我们表明，由酪氨酸降解引起的反应性中间体产生的内代谢应激会触发AIP-1基因的表达，这对于对环境毒素砷的反应至关重要，并且对不稳定的多谷氨酰胺的清除和β蛋白的清除至关重要。 AIP-1通过与蛋白质体结合并增强蛋白质体功能起作用。我们发现，AIP-1的完全诱导取决于氧化应力响应性SKN-1转录因子，但在没有SKN-1的情况下仍然存在明显的诱导。重要的是，用WDR-23（RNAi）激活SKN-1（显着诱导其他SKN-1靶基因的表达）会产生AIP-1表达的最小增加。这表明先前在AIP-1/AIRAP诱导中证明的特异性可以反映多种协同激活剂的作用，例如热休克因子同源性HSF-1，我们也发现这是完全诱导所必需的。这些事件可以通过蛋白体功能障碍触发，因为我们发现此事件链接了AIP-1的多个诱导剂。总之，我们的结果表明，细胞应力通过SKN-1依赖性和非依赖性途径触发AIP-1的表达。
Maintenance of a stable, properly folded, and catalytically active proteome is a major challenge to organisms in the face of multiple internal and external stresses which damage proteins and lead to protein misfolding. Here we show that internal metabolic stress produced by reactive intermediates resulting from tyrosine degradation triggers the expression of the aip-1 gene, which is critical in responses to the environmental toxin arsenic and the clearance of unstable polyglutamine and A beta proteins. aip-1 acts via binding to the proteosome and enhancing proteosomal function. We find that full induction of aip-1 depends on the oxidative-stress-responsive skn-1 transcription factor but significant induction still occurs without skn-1. Importantly, activation of skn-1 with wdr-23(RNAi), which dramatically induces the expression of other skn-1 target genes, produces a minimal increase in aip-1 expression. This suggests that the previously demonstrated specificity in aip-1/AIRAP induction could reflect the actions of multiple synergistic activators, such as the heat shock factor homolog hsf-1, which we also find is required for full induction. These may be triggered by proteosome dysfunction, as we find that this event links the multiple inducers of aip-1. Together, our results show that cell stress triggers aip-1 expression by both skn-1-dependent and -independent pathways.