Subcellular dynamics of the VHL tumor suppressor: On the move for HIF degradation

The von Hippel-Lindau (VHL) tumor suppressor protein, the recognition component of an E3 ubiquitin ligase complex, recruits the α-subunit of the hypoxia-inducible factor (HIFα) for oxygen-dependent degradation. The ability of VHL to mediate efficient degradation of HIFα is also dependent on its oxygen/pH-regulated subcellular trafficking. Under aerobic conditions, VHL engages in nuclear-cytoplasmic trafficking that requires ongoing transcription and is mediated by a novel nuclear export motif, the transcription-dependent nuclear export motif (TD-NEM). Disease-causing mutations targeting TD-NEM restrain VHL from mediating efficient oxygen-dependent degradation of HIFα by altering its subcellular dynamics. In addition, decreasing the extracellular pH, during anaerobic metabolism, stabilizes HIFα by triggering the relocalization and static detention of VHL to nucleoli. Together, these recent findings support the critical role of subcellular trafficking and dynamic properties for the function of VHL in promoting HIF regulation and tumor suppression.