Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.
Aging Cell. 2018 Oct;17(5):e12813. doi: 10.1111/acel.12813. Epub 2018 Jul 12.
Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat-shock response (HSR) is a conserved survival mechanism mediated by the transcription factor HSF1 which functions to maintain proteostasis. In mammalian cells, HSF1 is regulated by a variety of factors including the prolongevity factor SIRT1. SIRT1 promotes the DNA-bound state of HSF1 through deacetylation of the DNA-binding domain of HSF1, thereby enhancing the HSR. SIRT1 is also regulated by various factors, including negative regulation by the cell-cycle and apoptosis regulator CCAR2. CCAR2 negatively regulates the HSR, possibly through its inhibitory interaction with SIRT1. We were interested in studying conservation of the SIRT1/CCAR2 regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the HSF1 homolog, HSF-1. We have uncovered that negative regulation of the HSR by CCAR2 is conserved in C. elegans and is mediated by the CCAR2 ortholog, CCAR-1. This negative regulation requires the SIRT1 homolog SIR-2.1. In addition, knockdown of CCAR-1 via ccar-1 RNAi works through SIR-2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism.
蛋白质质量控制缺陷是许多人类疾病的核心，我们需要制定策略，以更好地理解控制蛋白质组质量的机制。热休克反应（HSR）是一种由转录因子 HSF1 介导的保守生存机制，其功能是维持蛋白质的稳定。在哺乳动物细胞中，HSF1 受到多种因素的调节，包括长寿因子 SIRT1。SIRT1 通过去乙酰化 HSF1 的 DNA 结合域来促进 HSF1 的 DNA 结合状态，从而增强 HSR。SIRT1 还受到多种因素的调节，包括细胞周期和凋亡调节剂 CCAR2 的负调控。CCAR2 通过与 SIRT1 的抑制性相互作用负调控 HSR。我们有兴趣研究 SIRT1/CCAR2 调节相互作用在秀丽隐杆线虫中的保守性，并利用该模式生物观察调节 Sirtuin 活性对 HSR、寿命和蛋白质组稳定的影响。HSR 在秀丽隐杆线虫中高度保守，由 HSF1 同源物 HSF-1 介导。我们已经发现，CCAR2 对 HSR 的负调控在秀丽隐杆线虫中是保守的，由 CCAR2 同源物 CCAR-1 介导。这种负调控需要 SIRT1 同源物 SIR-2.1。此外，通过 ccar-1 RNAi 敲低 CCAR-1 通过 SIR-2.1 增强应激抗性、运动性、寿命和蛋白质组稳定。因此，这项工作突出了增强 Sirtuin 活性以促进整个生物体 HSR 的益处。
