title: The N-Terminal Domain of SIRT1 Is a Positive Regulator of Endogenous SIRT1-Dependent Deacetylation and Transcriptional Outputs.
abstract: The NAD+-dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Ghisays
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Brace
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Yackly
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Hyock Joo
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Mills
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Kashentseva
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: imaishin@wustl.edu.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Imai
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: tome@wustl.edu.
authors.forename: Tom
authors.initials: T
authors.lastname: Ellenberger