Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization

Cell Death Differ. 2017 Jun;24(6):961-970. doi: 10.1038/cdd.2016.119. Epub 2017 Jan 6.

Abstract

PCAF and ADA3 associate within the same macromolecular complexes to control the transcription of many genes, including some that regulate apoptosis. Here we show that PCAF and ADA3 regulate the expression of PACS1, whose protein product is a key component of the machinery that sorts proteins among the trans-Golgi network and the endosomal compartment. We describe a novel role for PACS1 as a regulator of the intrinsic pathway of apoptosis and mitochondrial outer membrane permeabilization. Cells with decreased PACS1 expression were refractory to cell death mediated by a variety of stimuli that operate through the mitochondrial pathway, including human granzyme B, staurosporine, ultraviolet radiation and etoposide, but remained sensitive to TRAIL receptor ligation. The mitochondria of protected cells failed to release cytochrome c as a result of perturbed oligomerization of BAX and BAK. We conclude that PCAF and ADA3 transcriptionally regulate PACS1 and that PACS1 is a key regulator of BAX/BAK oligomerization and the intrinsic (mitochondrial) pathway to apoptosis.

MeSH terms

  • Apoptosis*
  • Cell Line
  • Epigenesis, Genetic*
  • Granzymes
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Protein Multimerization
  • Signal Transduction*
  • Staurosporine
  • Transcription Factors / metabolism*
  • Ultraviolet Rays
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / metabolism
  • p300-CBP Transcription Factors / metabolism*

Substances

  • BAK1 protein, human
  • BAX protein, human
  • PACS1 protein, human
  • TADA3 protein, human
  • Transcription Factors
  • Vesicular Transport Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • GZMB protein, human
  • Granzymes
  • Staurosporine