Tomita Takuya, Hamazaki Jun, Hirayama Shoshiro, McBurney Michael W, Yashiroda Hideki, Murata Shigeo
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Center for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Sci Rep. 2015 Jul 29;5:12613. doi: 10.1038/srep12613.
Protein quality control is an important mechanism to maintain cellular homeostasis. Damaged proteins have to be restored or eliminated by degradation, which is mainly achieved by molecular chaperones and the ubiquitin-proteasome system. The NAD(+)-dependent deacetylase Sirt1 has been reported to play positive roles in the regulation of cellular homeostasis in response to various stresses. However, its contribution to protein quality control remains unexplored. Here we show that Sirt1 is involved in protein quality control in both an Hsp70-dependent and an Hsp70-independent manner. Loss of Sirt1 led to the accumulation of ubiquitinated proteins in cells and tissues, especially upon heat stress, without affecting proteasome activities. This was partly due to decreased basal expression of Hsp70. However, this accumulation was only partially alleviated by overexpression of Hsp70 or induction of Hsp70 upon heat shock in Sirt1-deficient cells and tissues. These results suggest that Sirt1 mediates both Hsp70-dependent and Hsp70-independent protein quality control. Our findings cast new light on understanding the role of Sirt1 in maintaining cellular homeostasis.
蛋白质质量控制是维持细胞内稳态的重要机制。受损蛋白质必须通过降解来修复或清除，这主要由分子伴侣和泛素-蛋白酶体系统来实现。据报道，NAD(+)依赖性脱乙酰酶Sirt1在响应各种应激时对细胞内稳态的调节中发挥积极作用。然而，其对蛋白质质量控制的贡献仍未得到探索。在这里，我们表明Sirt1以依赖Hsp70和不依赖Hsp70的方式参与蛋白质质量控制。Sirt1的缺失导致细胞和组织中泛素化蛋白质的积累，尤其是在热应激时，而不影响蛋白酶体活性。这部分是由于Hsp70的基础表达降低。然而，在Sirt1缺陷的细胞和组织中，Hsp70的过表达或热休克时Hsp70的诱导只能部分缓解这种积累。这些结果表明，Sirt1介导依赖Hsp70和不依赖Hsp70的蛋白质质量控制。我们的发现为理解Sirt1在维持细胞内稳态中的作用提供了新的线索。
