DJ-1 activates SIRT1 through its direct binding to SIRT1

Abstract

The DJ-1 gene is a ras-dependent oncogene and also a causative gene for a familial form of Parkinson's disease park7. DJ-1 is a multi-functional protein and plays roles in regulation of cell growth, cells death, metabolism and mitochondrial homeostasis against oxidative stress. To explore various functions, DJ-1 associates with a number of proteins localized in the nucleus, cytoplasm and mitochondria. The oxidative status of a cysteine residue at an amino acid number 106 (C106) of DJ-1 determines the active level of DJ-1. Precise molecular mechanism of exploration of DJ-1 function is, however, not resolved. In this study, we identified Sirtuin family proteins (SIRT1, 2, and 4-6) as DJ-1-binding proteins, and DJ-1 associated with SIRT1 in cells. Sirtuins like DJ-1 also regulates growth, death and metabolism of cells and mitochondrial homeostasis. We found that DJ-1 stimulated deacetylase activity of SIRT1 and that SIRT1-suppressed transcriptional activity of SIRT1-target p53 was further decreased by DJ-1. Furthermore, SIRT1 activity was reduced in DJ-1-knockout cells, and this reduced activity was restored by re-introduction of wild-type DJ-1 but not of C106-mutant DJ-1 into DJ-1-knockout cells. It is first report showing direct connection of DJ-1 with SIRT1.