RRC ID 28624
Author Sakamoto T, Seiki M.
Title Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1.
Journal J Biol Chem
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.
Volume 284(44)
Pages 30350-9
Published 2009-10-30
DOI 10.1074/jbc.M109.019216
PII M109.019216
PMID 19726677
PMC PMC2781590
MeSH 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*
IF 4.238
Times Cited 36
DNA material pENTR Mint3/APBA3 (RDB08028)