Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity

Cell Rep. 2017 Mar 28;18(13):3069-3077. doi: 10.1016/j.celrep.2017.03.012.

Abstract

The conserved NAD+-dependent deacylase SIRT1 plays pivotal, sometimes contrasting, roles in diverse physiological and pathophysiological conditions. In this study, we uncover a tissue-restricted isoform of SIRT1 (SIRT1-ΔE2) that lacks exon 2 (E2). Candidate-based screening of SIRT1 substrates demonstrated that the domain encoded by this exon plays a key role in specifying SIRT1 protein-protein interactions. The E2 domain of SIRT1 was both necessary and sufficient for PGC1α binding, enhanced interaction with p53, and thus downstream functions. Since SIRT1-FL and SIRT1-ΔE2 were found to have similar intrinsic catalytic activities, we propose that the E2 domain tethers specific substrate proteins. Given the absence of SIRT1-ΔE2 in liver, our findings provide insight into the role of the E2 domain in specifying "metabolic functions" of SIRT1-FL. Identification of SIRT1-ΔE2 and the conserved specificity domain will enhance our understanding of SIRT1 and guide the development of therapeutic interventions.

Keywords: AKT; DNA damage; E2; PGC1α; PPARα; SIRT1; SIRT1-Δ; insulin signaling; isoform; p53; specificity domain; β-oxidation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocatalysis
  • Cattle
  • Conserved Sequence
  • Evolution, Molecular
  • Exons / genetics
  • Fatty Acids / metabolism
  • Gene Expression Regulation
  • Mice
  • Mutant Proteins / metabolism
  • Organ Specificity*
  • Oxidation-Reduction
  • Protein Binding
  • Protein Domains
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Multimerization
  • Sirtuin 1 / chemistry*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Structure-Activity Relationship
  • Subcellular Fractions / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Fatty Acids
  • Mutant Proteins
  • Protein Isoforms
  • Tumor Suppressor Protein p53
  • Sirtuin 1