FBXO22 protein is required for optimal synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine

J Biol Chem. 2014 Dec 5;289(49):33904-15. doi: 10.1074/jbc.M114.618405. Epub 2014 Oct 21.


d-Serine is a physiological activator of NMDA receptors (NMDARs) in the nervous system that mediates several NMDAR-mediated processes ranging from normal neurotransmission to neurodegeneration. d-Serine is synthesized from l-serine by serine racemase (SR), a brain-enriched enzyme. However, little is known about the regulation of d-serine synthesis. We now demonstrate that the F-box only protein 22 (FBXO22) interacts with SR and is required for optimal d-serine synthesis in cells. Although FBXO22 is classically associated with the ubiquitin system and is recruited to the Skip1-Cul1-F-box E3 complex, SR interacts preferentially with free FBXO22 species. In vivo ubiquitination and SR half-life determination indicate that FBXO22 does not target SR to the proteasome system. FBXO22 primarily affects SR subcellular localization and seems to increase d-serine synthesis by preventing the association of SR to intracellular membranes. Our data highlight an atypical role of FBXO22 in enhancing d-serine synthesis that is unrelated to its classical effects as a component of the ubiquitin-proteasome degradation pathway.

Keywords: F-box Proteins; FBXO22; Glutamate Receptor; NMDA Receptor; Neurotransmitter; Neurotransmitter Receptor; Serine Racemase; Ubiquitin; Ubiquitylation (Ubiquitination); d-Serine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • F-Box Proteins / antagonists & inhibitors
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Gene Expression Regulation
  • Half-Life
  • Humans
  • Intracellular Membranes / metabolism
  • Neuroglia / cytology
  • Neuroglia / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Racemases and Epimerases / genetics
  • Racemases and Epimerases / metabolism*
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Serine / biosynthesis*
  • Signal Transduction
  • Ubiquitination


  • F-Box Proteins
  • FBXO22 protein, human
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Serine
  • Proteasome Endopeptidase Complex
  • Racemases and Epimerases
  • serine racemase