PDF(Pubmed)
Abstract：
The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, limiting Coenzyme A levels in C. elegans and in human cells, by inhibiting the conserved pantothenate kinase, promotes proteostasis. Impairment of the cytosolic iron-sulfur clusters formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by Coenzyme A/iron-sulfur cluster deficiencies are dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis promoting factor. This reflects the versatile nature of this conserved transcription factor, that can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases.
摘要：
正确折叠的蛋白质组的维持对于细胞功能和机体健康至关重要。其年龄依赖性崩溃与多种疾病相关。这里,我们发现，尽管辅酶A作为分子辅因子在数百种细胞反应中起着核心作用，限制秀丽隐杆线虫和人类细胞中的辅酶A水平，通过抑制保守的泛酸激酶，促进蛋白质稳定。胞质铁硫簇形成途径的损害，这取决于辅酶A，类似地促进蛋白质稳定并在同一途径中起作用。辅酶A/铁-硫簇缺乏对蛋白质稳定的改善依赖于保守的HLH-30/TFEB转录因子。引人注目的是，在这些条件下,HLH-30通过增强选择伴侣基因的表达来促进蛋白质稳定，从而提供伴侣介导的蛋白质稳定屏蔽，而不是由于其作为自噬和溶酶体生物发生促进因子的作用。这反映了这种保守转录因子的多功能性，可以转录激活广泛的蛋白质质量控制机制，包括伴侣和应激反应基因以及自噬和溶酶体生物发生基因。这些结果突出了TFEB作为关键的促进蛋白质停滞的转录因子，并强调了它及其上游调节因子作为蛋白质停滞相关疾病的潜在治疗靶标。
