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Published 29 August 2005. doi:10.1083/jcb.200506030
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 5, 733-744
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Article

 Regulation of ubiquitin ligase dynamics by the nucleolus

Karim Mekhail1, Mireille Khacho1, Amanda Carrigan2, Robert R.J. Hache2, Lakshman Gunaratnam1, and Stephen Lee1

1 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
2 Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada

Correspondence to Stephen Lee: slee{at}uottawa.ca

Cellular pathways relay information through dynamic protein interactions. We have assessed the kinetic properties of the murine double minute protein (MDM2) and von Hippel-Lindau (VHL) ubiquitin ligases in living cells under physiological conditions that alter the stability of their respective p53 and hypoxia-inducible factor substrates. Photobleaching experiments reveal that MDM2 and VHL are highly mobile proteins in settings where their substrates are efficiently degraded. The nucleolar architecture converts MDM2 and VHL to a static state in response to regulatory cues that are associated with substrate stability. After signal termination, the nucleolus is able to rapidly release these proteins from static detention, thereby restoring their high mobility profiles. A protein surface region of VHL's ß-sheet domain was identified as a discrete [H+]-responsive nucleolar detention signal that targets the VHL/Cullin-2 ubiquitin ligase complex to nucleoli in response to physiological fluctuations in environmental pH. Data shown here provide the first evidence that cells have evolved a mechanism to regulate molecular networks by reversibly switching proteins between a mobile and static state.

Abbreviations used in this paper: ActD, actinomycin D; AP, acidification-permissive; B23, rRNA processing-factor nucleophosmin; FIB, rRNA processing factor fibrillarin; FLIP, fluorescence loss in photobleaching; HIF, hypoxia-inducible factor; iFRAP, inverse FRAP; MDM2, murine double minute protein; NES, nuclear export sequence; NoDSH+, [H+]-responsive nucleolar detention signal; NoLS, nucleolar localization sequence; NoRS, nucleolar retention sequence; PEG, polyethylene glycol; RS, ribosomal stress; SD media, standard media; VHL, von Hippel-Lindau.


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