Hypoxia-mediated Na-K-ATPase degradation requires von Hippel Lindau protein

Guofei Zhou, Laura A. Dada, Navdeep S. Chandel, Kazuhiro Iwai, Emilia Lecuona, Aaron Ciechanover, Jacob I. Sznajder

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Hypoxia inhibits Na-K-ATPase activity and leads to its degradation in mammalian cells. Von Hippel Lindau protein (pVHL) and hypoxia inducible factor (HIF) are key mediators in cellular adaptation to hypoxia; thus, we set out to investigate whether pVHL and HIF participate in the hypoxia-mediated degradation of plasma membrane Na-K-ATPase. We found that in the presence of pVHL hypoxia decreased Na-K-ATPase activity and promoted the degradation of plasma membrane Na-K-ATPase. In pVHL-deficient cells, hypoxia did not decrease the Na-K-ATPase activity and the degradation of plasma membrane Na-K-ATPase was prevented. pVHL-mediated degradation of Na-K-ATPase required the functional pVHL E3 ligase and Ubc5 since pVHL mutants and dominant-negative Ubc5 prevented Na-K-ATPase from degradation. The generation of reactive oxygen species was necessary for pVHL-mediated Na-K-ATPase degradation during hypoxia. Desferrioxamine, which stabilizes HIF1/2α, did not affect the half-life of plasma membrane Na-K-ATPase. In addition, stabilizing HIF1/2α by infecting mammalian cells with adenoviruses containing the oxygen-dependent degradation domain of HIF1α did not affect the plasma membrane Na-K-ATPase degradation. In cells with suppression of pVHL by short hairpin RNA, the Na-K-ATPase was not degraded during hypoxia, whereas cells with knockdown of HIF1/2α retained the ability to degrade plasma membrane Na-K-ATPase. These findings suggest that pVHL participates in the hypoxia-mediated degradation of plasma membrane Na-K-ATPase in a HIFindependent manner.

Original languageEnglish (US)
Pages (from-to)1335-1342
Number of pages8
JournalFASEB Journal
Volume22
Issue number5
DOIs
StatePublished - May 2008

Keywords

  • Hypoxia inducible factor
  • pVHL

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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