SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia.
SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1(-/-) embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1(-/-) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.
Cheng
Jinke
J
Department of Cardiology, The University of Texas MD Anderson Cancer Center, The University of Texas, Houston Health Science Center, Houston, TX 77030, USA.
Kang
Xunlei
X
Zhang
Sui
S
Yeh
Edward T H
ET
D000740:Anemia / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D003546:Cysteine Endopeptidases; D004622:Embryo, Mammalian / Q000473:pathology; D010450:Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000166:cytology; D004920:Erythropoiesis; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D013816:Thermodynamics; D014158:Transcription, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse; D046988:Proteasome Endopeptidase Complex