p53 cooperates with SIRT6 to regulate cardiolipin de novo biosynthesis

Cell Death Dis. 2018 Sep 20;9(10):941. doi: 10.1038/s41419-018-0984-0.

Abstract

The tumor suppressor p53 has critical roles in regulating lipid metabolism, but whether and how p53 regulates cardiolipin (CL) de novo biosynthesis is unknown. Here, we report that p53 physically interacts with histone deacetylase SIRT6 in vitro and in vivo, and this interaction increases following palmitic acid (PA) treatment. In response to PA, p53 and SIRT6 localize to chromatin in a p53-dependent manner. Chromatin p53 and SIRT6 bind the promoters of CDP-diacylglycerol synthase 1 and 2 (CDS1 and CDS2), two enzymes required to catalyze CL de novo biosynthesis. Here, SIRT6 serves as a co-activator of p53 and effectively recruits RNA polymerase II to the CDS1 and CDS2 promoters to enhance CL de novo biosynthesis. Our findings reveal a novel, cooperative model executed by p53 and SIRT6 to maintain lipid homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cardiolipins / metabolism*
  • Diacylglycerol Cholinephosphotransferase / genetics
  • Diacylglycerol Cholinephosphotransferase / metabolism
  • HCT116 Cells
  • Hep G2 Cells
  • Humans
  • Immunoprecipitation
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Real-Time Polymerase Chain Reaction
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cardiolipins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • CDS1 protein, human
  • CDS2 protein, human
  • Diacylglycerol Cholinephosphotransferase
  • SIRT6 protein, human
  • Sirtuins