mAKAP compartmentalizes oxygen-dependent control of HIF-1alpha.
The activity of the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) is increased in response to reduced intracellular oxygen. Enzymes of the protein ubiquitin machinery that signal the destruction or stabilization of HIF-1alpha tightly control this transcriptional response. Here, we show that muscle A kinase-anchoring protein (mAKAP) organized ubiquitin E3 ligases that managed the stability of HIF-1alpha and optimally positioned it close to its site of action inside the nucleus. Functional experiments in cardiomyocytes showed that depletion of mAKAP or disruption of its targeting to the perinuclear region altered the stability of HIF-1alpha and transcriptional activation of genes associated with hypoxia. Thus, we propose that compartmentalization of oxygen-sensitive signaling components may influence the fidelity and magnitude of the hypoxic response.
Wong
Wei
W
1Howard Hughes Medical Institute and Vollum Institute, Oregon Health & Science University, 3181 S. W. Sam Jackson Park Road, Portland, OR 97239, USA.
Goehring
April S
AS
Kapiloff
Michael S
MS
Langeberg
Lorene K
LK
Scott
John D
JD
D054758:A Kinase Anchor Proteins / Q000502:physiology*; D002451:Cell Compartmentation; D002460:Cell Line; D002467:Cell Nucleus; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010100:Oxygen / Q000502:physiology*; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D054758:A Kinase Anchor Proteins; C093173:AKAP6 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D044767:Ubiquitin-Protein Ligases; D010100:Oxygen