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

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-Fbox 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 ubiquitinproteasome degradation pathway.