Major vault protein forms complexes with hypoxia-inducible factor (HIF)-1α and reduces HIF-1α level in ACHN human renal adenocarcinoma cells

Vaults are evolutionarily highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. Although roles in multidrug resistance and innate immunity have been suggested, the physiological function of vaults remains unclear. Major vault protein (MVP), the main component of the vault particle, has been reported to be induced by hypoxia. However, there are no reports about the effect of vaults on cellular responses to hypoxia. We thus examined whether vaults are implicated in cellular responses to hypoxia. In this study, we focused on hypoxia-inducible factor-1 alpha (HIF-1 alpha), which is a master regulator of hypoxic responses, and found that: (i) MVP knockdown by RNA interference increases HIF-1 alpha protein levels induced by hypoxia and hypoxia mimetics; (ii) MVP knockdown does not affect HIF-1 alpha mRNA levels, but decreases the ubiquitination and degradation of HIF-1 alpha protein; and (iii) vaults form complexes with HIF-1 alpha, PHD2, and pVHL. Taken together, these results suggest that vaults function as scaffolds in HIF-1 alpha degradation pathway and promote the ubiquitination and degradation of HIF-1 alpha. (Cancer Sci 2010; 101: 920-926)