PROTEIN DEGRADATION Dual Roles of VHL

Under low oxygen conditions, hypoxia inducible transcription factors (HIFs) regulate processes such as vascular tone, metabolism, and neoangiogenesis to adapt to the stressful condition. However, under normal oxygen tension, these factors are hydroxylated, a modification that signals ubiquitination and subsequent degradation of HIFs by the 26S proteasome complex. This pathway to destruction involves direct association between HIF and the tumor suppressor protein von Hippel-Lindau (VHL), which itself is associated with an E3 ubiquitin ligase complex called VBC/Cul-2. VHL and VBC/Cul-2 are known to shuttle between the nucleus and cytoplasm. Groulx and Lee report that oxygen-dependent destruction of HIF-1 requires shuttling of VHL. VHL engaged in a constitutive shuttle that was insensitive to oxygen conditions or to the expression levels of HIF-1. When cells were shifted to normal oxygen conditions, HIF-1 accumulated in the nucleus where VHL mediated HIF-1 ubiquitination. This modification in the nucleus was required for HIF-1 export, as observed by cell fractionation and immunofluorescence. VHL was only associated with ubiquitinated HIF-1 in the nucleus. The authors propose that VHL serves not only to bring a substrate into association with a ubiquitin ligase under hypoxic conditions, but its nuclear-cytoplasmic dynamic is critical for substrate export and final destruction.

I. Groulx, S. Lee, Oxygen-dependent ubiquitin and degradation of hypoxia-inducible factor require nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein. Mol. Cell. Biol. 22, 5319-5336 (2002). [Abstract] [Full Text]