Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1

J Biol Chem. 2009 Oct 30;284(44):30350-9. doi: 10.1074/jbc.M109.019216. Epub 2009 Sep 2.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor regulating cellular responses to hypoxia and is composed of alpha and beta subunits. During normoxia, factor inhibiting HIF-1 (FIH-1) inhibits the activity of HIF-1 by preventing HIF-1alpha binding to p300/CBP via modification of the Asn(803) residue. However, it is not known whether FIH-1 activity can be regulated in an oxygen-independent manner. In this study, we survey possible binding proteins to FIH-1 and identify Mint3/APBA3, which has been reported to bind Alzheimer beta-amyloid precursor protein. Purified Mint3 binds FIH-1 and inhibits the ability of FIH-1 to modify HIF-1alpha in vitro. In a reporter assay, the activity of HIF-1alpha is suppressed because of endogenous FIH-1 in HEK293 cells, and expression of Mint3 antagonizes this suppression. Macrophages are known to depend on glycolysis for ATP production because of elevated HIF-1 activity. FIH-1 activity is suppressed in macrophages by Mint3 so as to maintain HIF-1 activity. FIH-1 forms a complex with Mint3, and these two factors co-localize within the perinuclear region. Knockdown of Mint3 expression in macrophages leads to redistribution of FIH-1 to the cytoplasm and decreases glycolysis and ATP production. Thus, Mint3 regulates the FIH-1-HIF-1 pathway, which controls ATP production in macrophages and therefore represents a potential new therapeutic target to regulate macrophage-mediated inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenosine Triphosphate / biosynthesis
  • Carrier Proteins / physiology*
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1 / agonists
  • Hypoxia-Inducible Factor 1 / metabolism
  • Macrophages / metabolism*
  • Mixed Function Oxygenases
  • Protein Binding
  • Protein Transport
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / metabolism*

Substances

  • APBA3 protein, human
  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Hypoxia-Inducible Factor 1
  • Repressor Proteins
  • Adenosine Triphosphate
  • Mixed Function Oxygenases
  • HIF1AN protein, human