title: FBXO22 protein is required for optimal synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine.
abstract: 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.
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Dikopoltsev
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Veronika N
authors.initials: VN
authors.lastname: Foltyn
authors.affiliation: the Department of Pharmacognosy, University of Vienna, 1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Zehl
authors.affiliation: the Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark, and.
authors.forename: Ole N
authors.initials: ON
authors.lastname: Jensen
authors.affiliation: the Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Radzishevsky
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel, hwolosker@tx.technion.ac.il.
authors.forename: Herman
authors.initials: H
authors.lastname: Wolosker
mesh_terms: D045744:Cell Line, Tumor; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006207:Half-Life; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis*; D015398:Signal Transduction; D054875:Ubiquitination; D000099300:Serine Racemase
chemical_list: D044783:F-Box Proteins; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering; D019998:Racemases and Epimerases; D018160:Receptors, Cytoplasmic and Nuclear; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D012694:Serine; D000099300:Serine Racemase; C561886:FBXO22 protein, human
keywords: F-box Proteins; FBXO22; Glutamate Receptor; NMDA Receptor; Neurotransmitter; Neurotransmitter Receptor; Serine Racemase; Ubiquitin; Ubiquitylation (Ubiquitination); d-Serine