J Biol Chem. 2021 Jun 30. pii: S0021-9258(21)00729-8. [Epub ahead of print]
100929
Yuanyuan Huang,
Jianlin Lu,
Li Zhan,
Ming Wang,
Ronghua Shi,
Xiao Yuan,
Xinjiao Gao,
Xing Liu,
Jianye Zang,
Wei Liu,
Xuebiao Yao.
The NAD+-dependent deacetylase Sirt1 has been implicated in the prevention of many age-related diseases, including cancer, type 2 diabetes, and cardiovascular disease. Resveratrol, a plant polyphenol, exhibits anti-aging, anti-tumor, and vascular protection effects by activating Sirt1. However, the molecular mechanism of Sirt1 activation as induced by resveratrol remains unclear. By knockdown/rescue experiments, flurometric Sirt1 activity assay, immunoprecipitation and pull-down assays, we identify here that the tumor suppressor LKB1 (liver kinase B1) as a direct activator of Sirt1 elicited by resveratrol. Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C-terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C-terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction. Functionally, LKB1-dependent Sirt1 activation increases mitochondrial biogenesis and respiration through deacetylation and activation of the transcriptional co-activator PGC-1α. These results identify Sirt1 as a context-dependent target of LKB1 and suggest that a resveratrol-stimulated LKB1-Sirt1 pathway plays a vital role in mitochondrial metabolism, a key physiological process contributes to numerous age-related diseases.
Keywords: LKB1; Sirt1; deacetylation; mitochondria; phosphorylation