pVHL mediates K63-linked ubiquitination of IKKβ, leading to IKKβ inactivation.
Nuclear factor (NF)-κB is a transcription factor that plays an important role in many biological functions. Regulation of NF-κB activity is complicated, and ubiquitination is essential for NF-κB activation. Hypoxia can activate NF-κB. However, the underlying mechanism remains unclear. pVHL is a tumour suppressor and functions as an adaptor of E3-ligase. In this study, we demonstrated that pVHL inhibits NF-κB by mediating K63-ubiquitination of IKKβ, which is dependent on oxygen. We found that pVHL mediates K63-linked ubiquitination of IKKβ, which is an upstream regulator of NF-κB. The pVHL-mediated K63-ubiquitination of IKKβ prevents TAK1 binding, which leads to the inhibition of IKKβ phosphorylation and NF-κB activation. pVHL-mediated K63-ubiquitination of IKKβ is inhibited under hypoxia. DMOG, which is a specific inhibitor of prolyl hydroxylases, also suppresses K63-ubiquitination of IKKβ. Prolyl hydroxylase (PHD) 1 enhances K63-ubiquitination of IKKβ and inhibits IKKβ phosphorylation. These results suggest a novel function for pVHL in mediating K63-linked ubiquitination of IKKβ, which plays a role in the regulation of IKK/NF-κB signalling. The results also provide new insight into the mechanism of NF-κB activation through hypoxia.
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, China.
Yuxin
Y
Wang
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, China.
Wenting
W
Zhao
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, China.
Qiang
Q
Gao
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, China.
Li
L
Fan
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, China.
Yanqing
Y
Qin
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China.
Hu
H
Zhou
Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Min
M
Li
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China. Electronic address: jfang@sibs.ac.cn.
Jing
J
Fang
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D015687:Cell Hypoxia; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008239:Lysine; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D054875:Ubiquitination / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051550:I-kappa B Kinase; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D010100:Oxygen; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099151:MAP Kinase Kinase Kinase 7; C447780:EGLN2 protein, human; C496560:IKBKB protein, human; C497446:VHL protein, human; C040947:oxalylglycine
IKKβ; Ubiquitination; pVHL