Cellular Degradation of 4-hydroxy-2-oxoglutarate Aldolase Leads to Absolute Deficiency in Primary Hyperoxaluria Type 3

FEBS Lett. 2016 May;590(10):1467-76. doi: 10.1002/1873-3468.12181. Epub 2016 May 10.

Abstract

Primary hyperoxaluria type-3 is characterized by increased oxalate production caused by mutations in the HOGA1 gene encoding 4-hydroxy-2-oxoglutarate aldolase (HOGA1). How the most commonly occurring mutations affect the cellular fates of the expressed HOGA1 mutants is still unknown. We show that two prevalent recombinant HOGA1 mutants are thermally unstable with evidence for chaperone-mediated degradation when expressed in E. coli. In stably transformed HEK-293 cells, protein expression of the Glu315 deletion mutant only becomes detectable during incubation with a 26S proteasome inhibitor. These findings suggest that failure of chaperone-assisted folding leads to targeted cellular degradation and an absolute absence of HOGA1 function.

Keywords: aldolase; primary hyperoxaluria; ubiquitin proteasome.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Stability
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • HEK293 Cells
  • Humans
  • Hyperoxaluria, Primary / genetics*
  • Molecular Chaperones / metabolism
  • Mutation*
  • Oxo-Acid-Lyases / chemistry*
  • Oxo-Acid-Lyases / genetics*
  • Oxo-Acid-Lyases / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis

Substances

  • Molecular Chaperones
  • Proteasome Endopeptidase Complex
  • Oxo-Acid-Lyases
  • 4-hydroxy-2-oxoglutarate aldolase