Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO

J Biol Chem. 2016 Feb 26;291(9):4732-41. doi: 10.1074/jbc.M115.684878. Epub 2015 Dec 24.

Abstract

AML1-ETO is the most common fusion oncoprotein causing acute myeloid leukemia (AML), a disease with a 5-year survival rate of only 24%. AML1-ETO functions as a rogue transcription factor, altering the expression of genes critical for myeloid cell development and differentiation. Currently, there are no specific therapies for AML1-ETO-positive AML. While known for decades to be the translational product of a chimeric gene created by the stable chromosome translocation t(8;21)(q22;q22), it is not known how AML1-ETO achieves its native and functional conformation or whether this process can be targeted for therapeutic benefit. Here, we show that the biosynthesis and folding of the AML1-ETO protein is facilitated by interaction with the essential eukaryotic chaperonin TRiC (or CCT). We demonstrate that a folding intermediate of AML1-ETO binds to TRiC directly, mainly through its β-strand rich, DNA-binding domain (AML-(1-175)), with the assistance of HSP70. Our results suggest that TRiC contributes to AML1-ETO proteostasis through specific interactions between the oncoprotein's DNA-binding domain, which may be targeted for therapeutic benefit.

Keywords: AML1-ETO; TRiC/CCT; chaperone; chaperonin; fusion protein; leukemia; protein folding.

Publication types

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

MeSH terms

  • Animals
  • Cattle
  • Cell Survival
  • Chaperonin Containing TCP-1 / antagonists & inhibitors
  • Chaperonin Containing TCP-1 / chemistry
  • Chaperonin Containing TCP-1 / metabolism*
  • Core Binding Factor Alpha 2 Subunit / chemistry
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Immunoprecipitation
  • Models, Molecular*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism*
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Conformation
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Protein Stability
  • Protein Subunits
  • RUNX1 Translocation Partner 1 Protein
  • Rats
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Reticulocytes / metabolism

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • HSP70 Heat-Shock Proteins
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Peptide Fragments
  • Protein Subunits
  • RUNX1 Translocation Partner 1 Protein
  • Recombinant Fusion Proteins
  • TCP1 protein, human
  • Chaperonin Containing TCP-1