Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1.
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.
Sakamoto
Takeharu
T
Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Tokyo 108-8639, Japan.
Seiki
Motoharu
M
D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D002352:Carrier Proteins / Q000502:physiology*; D006019:Glycolysis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000819:agonists / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D011485:Protein Binding; D021381:Protein Transport; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
C117536:APBA3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D051793:Hypoxia-Inducible Factor 1; D012097:Repressor Proteins; D000255:Adenosine Triphosphate; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human