Caspase-8 cleaves histone deacetylase 7 and abolishes its transcription repressor function

J Biol Chem. 2008 Jul 11;283(28):19499-510. doi: 10.1074/jbc.M800331200. Epub 2008 May 5.

Abstract

Caspase-8 is the initiator caspase of the extrinsic apoptosis pathway and also has a role in non-apoptotic physiologies. Identifying endogenous substrates for caspase-8 by using integrated bioinformatics and biological approaches is required to delineate the diverse roles of this caspase. We describe a number of novel putative caspase-8 substrates using the Prediction of Protease Specificity (PoPS) program, one of which is histone deacetylase 7 (HDAC7). HDAC7 is cleaved faster than any other caspase-8 substrate described to date. It is also cleaved in primary CD4+CD8+ thymocytes undergoing extrinsic apoptosis. By using naturally occurring caspase inhibitors that have evolved exquisite specificity at concentrations found within the cell, we could unequivocally assign the cleavage activity to caspase-8. Importantly, cleavage of HDAC7 alters its subcellular localization and abrogates its Nur77 repressor function. Thus we demonstrate a direct role for initiator caspase-mediated proteolysis in promoting gene transcription.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology
  • COS Cells
  • Caspase 8 / chemistry
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Caspase Inhibitors
  • Chlorocebus aethiops
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Mice
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Software*
  • Substrate Specificity / physiology
  • Transcription, Genetic / physiology*

Substances

  • Caspase Inhibitors
  • DNA-Binding Proteins
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Protease Inhibitors
  • Receptors, Steroid
  • Repressor Proteins
  • Caspase 8
  • HDAC7 protein, human
  • Hdac7 protein, mouse
  • Histone Deacetylases