School of Basic Medicine, Shandong University, Jinan, Shandong Province, China.
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China.
Aging Cell. 2019 Apr;18(2):e12900. doi: 10.1111/acel.12900. Epub 2019 Jan 8.
The mammalian Sirt1 deacetylase is generally thought to be a nuclear protein, but some pilot studies have suggested that Sirt1 may also be involved in orchestrating nucleolar functions. Here, we show that nucleolar stress response is a ubiquitous cellular reaction that can be induced by different types of stress conditions, and Sirt1 is an endogenous suppressor of nucleolar stress response. Using stable isotope labeling by amino acids in cell culture approach, we have identified a physical interaction of between Sirt1 and the nucleolar protein nucleophosmin, and this protein-protein interaction appears to be necessary for Sirt1 inhibition on nucleolar stress, whereas the deacetylase activity of Sirt1 is not strictly required. Based on the reported prerequisite role of nucleolar stress response in stress-induced p53 protein accumulation, we have also provided evidence suggesting that Sirt1-mediated inhibition on nucleolar stress response may represent a novel mechanism by which Sirt1 can modulate intracellular p53 accumulation independent of lysine deacetylation. This process may represent an alternative mechanism by which Sirt1 regulates functions of the p53 pathway.
哺乳动物的 Sirt1 去乙酰化酶通常被认为是一种核蛋白，但一些初步研究表明，Sirt1 可能也参与调节核仁功能。在这里，我们表明核仁应激反应是一种普遍存在的细胞反应，可以由不同类型的应激条件诱导，并且 Sirt1 是核仁应激反应的内源性抑制剂。使用稳定同位素标记的氨基酸在细胞培养方法中，我们已经鉴定出 Sirt1 和核仁蛋白核仁磷酸蛋白之间的物理相互作用，并且这种蛋白质-蛋白质相互作用似乎对于 Sirt1 抑制核仁应激是必需的，而 Sirt1 的去乙酰化酶活性不是严格必需的。基于报道的核仁应激反应在应激诱导的 p53 蛋白积累中的前提作用，我们还提供了证据表明，Sirt1 介导的核仁应激反应抑制可能代表了一种新的机制，通过该机制，Sirt1 可以独立于赖氨酸去乙酰化来调节细胞内 p53 积累。这个过程可能代表了 Sirt1 调节 p53 通路功能的另一种机制。
