FBXO22 Protein Is Required for Optimal Synthesis of the N-Methyl-d-Aspartate (NMDA) Receptor Coagonist d-Serine

Dikopoltsev, Elena; Foltyn, Veronika N.; Zehl, Martin; Jensen, Ole N.; Mori, Hisashi; Radzishevsky, Inna; Wolosker, Herman

doi:10.1074/jbc.m114.618405

Cited by 13 publications

(7 citation statements)

References 56 publications

(68 reference statements)

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“…Tan MK et al reports that FBXO22 could control the activity of KDM4A through targeting it for proteasomal turnover [ 31 ], by which FBXO22 regulates histone H3 lysine 9 and 36 methylation levels in cell cycle. Besides, a recent study indicates that FBXO22 is essential for optimal synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine [ 32 ]. Here, we provide evidence that FBXO22 is up-regulated and might be an oncogene in HCC.…”

Section: Discussionmentioning

confidence: 99%

F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

et al. 2015

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Kruppel-like factor 4 (KLF4), a member of the KLF family of transcription factors, has been considered as a crucial tumor suppressor in hepatocellular carcinoma (HCC). Using affinity purifications and mass spectrometry, we identified FBXO22, Cullin1 and SKP1 as interacting proteins of KLF4. We demonstrate that F-box only protein 22 (FBXO22) interacts with and thereby destabilizes KLF4 via polyubiquitination. As a result, FBXO22 could promote HCC cells proliferation both in vitro and in vivo. However, KLF4 deficiency largely blocked the proliferative roles of FBXO22. Importantly, FBXO22 expression was markedly increased in human HCC tissues, which was correlated with down-regulation of KLF4. Therefore, our results suggest that FBXO22 might be a major regulator of HCC development through direct degradation of KLF4.

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Section: Discussionmentioning

confidence: 99%

F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

et al. 2015

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“…Neuronal SR activity is reduced by interaction with the synaptic protein Stargazin (21). In neurons, D-serine synthesis is enhanced by FBXO22, which prevents the association of SR to intracellular membranes (22), and by Golga3, which reduces the degradation of SR by the ubiquitin system (23). SR knock-out (KO) mice display phenotypic abnormalities compatible with NMDAR hypofunction (24 -26).…”

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confidence: 99%

Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production

Kolodney

Dumin

Safory

et al. 2015

Journal of Biological Chemistry

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D-Serine is a physiological co-agonist that activates N-methyl D-aspartate receptors (NMDARs) and is essential for neurotransmission, synaptic plasticity, and behavior. D-Serine may also trigger NMDAR-mediated neurotoxicity, and its dysregulation may play a role in neurodegeneration. D-Serine is synthesized by the enzyme serine racemase (SR), which directly converts L-serine to D-serine. However, many aspects concerning the regulation of D-serine production under physiological and pathological conditions remain to be elucidated. Here, we investigate possible mechanisms regulating the synthesis of D-serine by SR in paradigms relevant to neurotoxicity. We report that SR undergoes nucleocytoplasmic shuttling and that this process is dysregulated by several insults leading to neuronal death, typically by apoptotic stimuli. Cell death induction promotes nuclear accumulation of SR, in parallel with the nuclear translocation of GAPDH and Siah proteins at an early stage of the cell death process. Mutations in putative SR nuclear export signals (NESs) elicit SR nuclear accumulation and its depletion from the cytosol. Following apoptotic insult, SR associates with nuclear GAPDH along with other nuclear components, and this is accompanied by complete inactivation of the enzyme. As a result, extracellular D-serine concentration is reduced, even though extracellular glutamate concentration increases severalfold. Our observations imply that nuclear translocation of SR provides a fail-safe mechanism to prevent or limit secondary NMDAR-mediated toxicity in nearby synapses.

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“…The C-terminus truncated form of DISC1 is unable to bind SR and induces its degradation and D-serine depletion (Ma et al, 2013). FBXO22, a component of the ubiquitin-proteasome system, also interacts with SR modifying its intracellular organization (see below) (Dikopoltsev et al, 2014).…”

Section: Sr Small Ligands and Protein Interactorsmentioning

confidence: 99%

The Energy Landscape of Human Serine Racemase

Raboni

Marchetti

Faggiano

et al. 2019

Front. Mol. Biosci.

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Human serine racemase is a pyridoxal 5′-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L-serine and D-serine and their dehydration to pyruvate and ammonia. As D-serine is the co-agonist of the N-methyl-D-aspartate receptors for glutamate, the most abundant excitatory neurotransmitter in the brain, the structure, dynamics, function, regulation and cellular localization of serine racemase have been investigated in detail. Serine racemase belongs to the fold-type II of the PLP-dependent enzyme family and structural models from several orthologs are available. The comparison of structures of serine racemase co-crystallized with or without ligands indicates the presence of at least one open and one closed conformation, suggesting that conformational flexibility plays a relevant role in enzyme regulation. ATP, Mg2+, Ca2+, anions, NADH and protein interactors, as well as the post-translational modifications nitrosylation and phosphorylation, finely tune the racemase and dehydratase activities and their relative reaction rates. Further information on serine racemase structure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human serine racemase allowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site.

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FBXO22 Protein Is Required for Optimal Synthesis of the N-Methyl-d-Aspartate (NMDA) Receptor Coagonist d-Serine

Cited by 13 publications

References 56 publications

F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production

The Energy Landscape of Human Serine Racemase

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