Acireductone dioxygenase 1 (ADI1) is regulated by cellular iron by a mechanism involving the iron chaperone, PCBP1, with PCBP2 acting as a potential co-chaperone

Biochim Biophys Acta Mol Basis Dis. 2020 Oct 1;1866(10):165844. doi: 10.1016/j.bbadis.2020.165844. Epub 2020 May 29.


The iron-containing protein, acireductone dioxygenase 1 (ADI1), is a dioxygenase important for polyamine synthesis and proliferation. Using differential proteomics, the studies herein demonstrated that ADI1 was significantly down-regulated by cellular iron depletion. This is important, since ADI1 contains a non-heme, iron-binding site critical for its activity. Examination of multiple human cell-types demonstrated a significant decrease in ADI1 mRNA and protein after incubation with iron chelators. The decrease in ADI1 after iron depletion was reversible upon incubation of cells with the iron salt, ferric ammonium citrate (FAC). A significant decrease in ADI1 mRNA levels was observed after 14 h of iron depletion. In contrast, the chelator-mediated reduction in ADI1 protein occurred earlier after 10 h of iron depletion, suggesting additional post-transcriptional regulation. The proteasome inhibitor, MG-132, prevented the iron chelator-mediated decrease in ADI1 expression, while the lysosomotropic agent, chloroquine, had no effect. These results suggest an iron-dependent, proteasome-mediated, degradation mechanism. Poly r(C)-binding protein (PCBPs) 1 and 2 act as iron delivery chaperones to other iron-containing dioxygenases and were shown herein for the first time to be regulated by iron levels. Silencing of PCBP1, but not PCBP2, led to loss of ADI1 expression. Confocal microscopy co-localization studies and proximity ligation assays both demonstrated decreased interaction of ADI1 with PCBP1 and PCBP2 under conditions of iron depletion using DFO. These data indicate PCBP1 and PCBP2 interact with ADI1, but only PCBP1 plays a role in ADI1 expression. In fact, PCBP2 appeared to play an accessory role, being involved as a potential co-chaperone.

Keywords: Acireductone dioxygenase; PCBP1; PCBP2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases / genetics
  • Dioxygenases / metabolism*
  • Down-Regulation
  • Gene Expression Regulation / drug effects
  • Humans
  • Iron / metabolism*
  • Leupeptins
  • Membrane Potential, Mitochondrial
  • Molecular Chaperones / drug effects
  • Molecular Chaperones / metabolism*
  • Proteasome Inhibitors / pharmacology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Reactive Oxygen Species / metabolism
  • Zinc / metabolism


  • DNA-Binding Proteins
  • Leupeptins
  • Molecular Chaperones
  • PCBP1 protein, human
  • PCBP2 protein, human
  • Proteasome Inhibitors
  • RNA-Binding Proteins
  • Reactive Oxygen Species
  • SCO1 protein, human
  • Iron
  • ADI1 protein, human
  • Dioxygenases
  • Zinc
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde