Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein

von Hippel–Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel–Lindau protein (pVHL). Here we show that pVHL, through its β-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an α-domain-dependent manner. This is the first function to be ascribed to the pVHL β-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease.

[1]  P. Smaglik,et al.  New perspectives , 2011, Nature.

[2]  M. Lerman,et al.  Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. , 1994, Human molecular genetics.

[3]  A. Kibel,et al.  Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C , 1995, Science.

[4]  D. Duan,et al.  Inhibition of transcription elongation by the VHL tumor suppressor protein , 1995, Science.

[5]  A. Kibel,et al.  Tumour suppression by the human von Hippel-Lindau gene product , 1995, Nature Medicine.

[6]  B. Ponder,et al.  Isolated familial pheochromocytoma as a variant of von Hippel-Lindau disease. , 1996, The Journal of clinical endocrinology and metabolism.

[7]  J. Caro,et al.  Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. , 1997, The Journal of biological chemistry.

[8]  M. Nagao,et al.  Activation of Hypoxia-inducible Factor-1; Definition of Regulatory Domains within the α Subunit* , 1997, The Journal of Biological Chemistry.

[9]  N. Chandel,et al.  Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  L. Neckers,et al.  Stabilization of wild-type p53 by hypoxia-inducible factor 1α , 1998, Nature.

[11]  W. Kaelin,et al.  Regulation of Hypoxia-Inducible mRNAs by the von Hippel-Lindau Tumor Suppressor Protein Requires Binding to Complexes Containing Elongins B/C and Cul2 , 1998, Molecular and Cellular Biology.

[12]  L. Huang,et al.  Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway , 1998 .

[13]  W. Kaelin,et al.  The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. , 1998, Genes & development.

[14]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[15]  W. Kaelin,et al.  The von Hippel-Lindau tumour suppressor protein: new perspectives. , 1999, Molecular medicine today.

[16]  Yuichi Makino,et al.  Regulation of the Hypoxia-inducible Transcription Factor 1α by the Ubiquitin-Proteasome Pathway* , 1999, The Journal of Biological Chemistry.

[17]  B. Zbar,et al.  Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. , 1999, The Journal of clinical investigation.

[18]  R. Klausner,et al.  Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Gstaiger,et al.  The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. , 1999, Genes & development.

[20]  W. Kaelin.  Cancer: Many vessels, faulty gene , 1999, Nature.

[21]  W. Kaelin,et al.  Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. , 1999, Science.