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Molecular and Cellular Biology, January 2008, p. 302-314, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01044-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cancer-Causing Mutations in a Novel Transcription-Dependent Nuclear Export Motif of VHL Abrogate Oxygen-Dependent Degradation of Hypoxia-Inducible Factor{triangledown} ,{dagger}

Mireille Khacho, Karim Mekhail,{ddagger} Karine Pilon-Larose, Josianne Payette, and Stephen Lee*

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5

Received 13 June 2007/ Returned for modification 27 July 2007/ Accepted 16 October 2007

It is thought that degradation of nuclear proteins by the ubiquitylation system requires nuclear-cytoplasmic trafficking of E3 ubiquitin ligases. The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate recognition component of a Cullin-2-containing E3 ubiquitin ligase that recruits hypoxia-inducible factor (HIF) for oxygen-dependent degradation. We demonstrated that VHL engages in nuclear-cytoplasmic trafficking that requires ongoing transcription to promote efficient HIF degradation. Here, we report the identification of a discreet motif, DXGX2DX2L, that directs transcription-dependent nuclear export of VHL and which is targeted by naturally occurring mutations associated with renal carcinoma and polycythemia in humans. The DXGX2DX2L motif is also found in other proteins, including poly(A)-binding protein 1, to direct its transcription-dependent nuclear export. We define DXGX2DX2L as TD-NEM (transcription-dependent nuclear export motif), since inhibition of transcription by actinomycin D or 5,6-dichlorobenzimidazole abrogates its nuclear export activity. Disease-causing mutations of key residues of TD-NEM restrain the ability of VHL to efficiently mediate oxygen-dependent degradation of HIF by altering its nuclear export dynamics without affecting interaction with its substrate. These results identify a novel nuclear export motif, further highlight the role of nuclear-cytoplasmic shuttling of E3 ligases in degradation of nuclear substrates, and provide evidence that disease-causing mutations can target subcellular trafficking.

* Corresponding author. Mailing address: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Phone: (613) 562-5800, ext. 8385. Fax: (613) 562-5636. E-mail: slee{at}uottawa.ca

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Cell Biology, Harvard University, Boston, MA 02115.

Molecular and Cellular Biology, January 2008, p. 302-314, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01044-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Khacho, M., Mekhail, K., Pilon-Larose, K., Pause, A., Cote, J., Lee, S. (2008). eEF1A Is a Novel Component of the Mammalian Nuclear Protein Export Machinery. Mol. Biol. Cell 19: 5296-5308 [Abstract] [Full Text]  


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