title: CHFR negatively regulates SIRT1 activity upon oxidative stress.
abstract: SIRT1, the NAD+-dependent protein deacetylase, controls cell-cycle progression and apoptosis by suppressing p53 tumour suppressor. Although SIRT1 is known to be phosphorylated by JNK1 upon oxidative stress and subsequently down-regulated, it still remains elusive how SIRT1 stability and activity are controlled. Here, we have unveiled that CHFR functions as an E3 Ub-ligase of SIRT1, responsible for its proteasomal degradation under oxidative stress conditions. CHFR interacts with and destabilizes SIRT1 by ubiquitylation and subsequent proteolysis. Such CHFR-mediated SIRT1 inhibition leads to the increase of p53 acetylation and its target gene transcription. Notably, CHFR facilitates SIRT1 destabilization when SIRT1 is phosphorylated by JNK1 upon oxidative stress, followed by prominent apoptotic cell death. Meanwhile, JNK inhibitor prevents SIRT1 phosphorylation, leading to elevated SIRT1 protein levels even in the presence of H2O2. Taken together, our results indicate that CHFR plays a crucial role in the cellular stress response pathway by controlling the stability and function of SIRT1.
authors.affiliation: School of Biological Sciences, Research Institute of Basic Sciences, IMCB, Seoul National University, Seoul 08826, Korea.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Research Institute of Basic Sciences, IMCB, Seoul National University, Seoul 08826, Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Kwon
authors.affiliation: School of Biological Sciences, Research Institute of Basic Sciences, IMCB, Seoul National University, Seoul 08826, Korea.
authors.forename: Jae Oh
authors.initials: JO
authors.lastname: Song
authors.affiliation: School of Biological Sciences, Research Institute of Basic Sciences, IMCB, Seoul National University, Seoul 08826, Korea.
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Bae
authors.affiliation: School of Biological Sciences, Research Institute of Basic Sciences, IMCB, Seoul National University, Seoul 08826, Korea.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seol
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D048055:Mitogen-Activated Protein Kinase 8; D046988:Proteasome Endopeptidase Complex; C447939:SIRT1 protein, human; D056564:Sirtuin 1