Diacylglycerol kinase δ destabilizes serotonin transporter protein through the ubiquitin-proteasome system

Lü, Qiang; Murakami, Chiaki; Hoshino, Fumi; Murakami, Yuki; Sakane, Fumio

doi:10.1016/j.bbalip.2019.158608

Cited by 13 publications

(20 citation statements)

References 41 publications

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“…Schematic representation of Praja‐1 and SERT regulation by DGKδ. DGKδ interacts with SERT [12], MAGE‐D1 [13], and Praja‐1 E3 ubiquitin‐protein ligase [13], which ubiquitinates SERT [14], and induced SERT degradation through the ubiquitin (Ub)–proteasome system in a DGK activity‐dependent manner [13]. In the present study, we revealed that DGKδ selectively phosphorylates 18:0/22:6‐DG to generate 18:0/22:6‐PA.…”

Section: Resultsmentioning

confidence: 99%

“…Mouse Praja‐1 (NCBI accession no. ) cDNA was amplified from mouse brain cDNA and inserted into the EcoRI/SalI sites of the pAcGFP vector [13]. To express glutathione S ‐transferase (GST)‐fused Praja‐1 in mammalian cells, Praja‐1 cDNA was also ligated into the EcoRI/XhoI sites of pSF‐CMV‐Puro‐NH2‐GST‐TEV (Oxford Genetics, Oxford, UK).…”

Section: Methodsmentioning

confidence: 99%

“…These results strongly suggested that OCD‐like behaviors in the DGKδ‐KO mice were caused by increased levels of SERT. Additionally, we recently found that DGKδ interacted with SERT [12,13], melanoma antigen gene‐D1 (MAGE‐D1) [13], and Praja‐1 E3 ubiquitin‐protein ligase [13], which ubiquitinates SERT [14], and induced SERT degradation through the Praja‐1–ubiquitin–proteasome system in a DGK activity‐dependent manner [13]. However, it remains unclear how Praja‐1 activity is controlled by DGKδ.…”

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confidence: 99%

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1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

Lü

Murakami

et al. 2020

FEBS Letters

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Edited by Sandro SonninoSerotonin transporter (SERT) is involved in serotonergic system regulation and in the pathophysiology/therapeutics of serotonin-/SERT-related diseases such as obsessive-compulsive disorder, depression, autism, and schizophrenia. We recently revealed that diacylglycerol (DG) kinase (DGK) d induces ubiquitination/degradation of SERT in a DGK activity-dependent manner through Praja-1 E3 ubiquitin-protein ligase. However, it is still unclear how Praja-1 activity is regulated by DGKd. Here, we reveal that 1-stearoyl-2-docosahexaenoyl (18:0/22:6)-phosphatidic acid (PA) and 18:0/22:6-DG are simultaneously decreased and accumulated, respectively, in the DGKd-knockout mouse brain, indicating that DGKd selectively phosphorylates 18:0/22:6-DG to generate 18:0/22:6-PA. Moreover, we find that 18:0/22:6-PA selectively binds to Praja-1 and enhances its activity. These results strongly suggest that 18:0/ 22:6-PA generated by DGKd activates Praja-1 to degrade SERT in the brain.Keywords: diacylglycerol kinase; docosahexaenoic acid; E3 ubiquitinprotein ligase; obsessive-compulsive disorder; Praja-1; serotonin transporter Serotonin/5-hydroxytryptamine (5-HT) is known to be involved in anxiety, depression, compulsiveness, and impulsivity [1]. The serotonin/5-HT transporter (SERT) reuptakes 5-HT from the synaptic cleft into the presynaptic neuron for recycling and metabolic degradation [2,3]. Selective serotonin reuptake (SERT) inhibitors (SSRIs) are used for the treatment of obsessive-compulsive disorder (OCD) [2,3] and major depressive disorder [4]. Several studies using SERTdeficient rodents have demonstrated that SERT is implicated in neurodevelopmental disorders, such as depression, anxiety, and autism [5]. Therefore, hyperfunction of SERT, which reduces the amount of 5-HT in the synaptic cleft, causes various psychiatric disorders mentioned above. However, the regulatory mechanisms of SERT function are still obscure.Diacylglycerol (DG) kinase (DGK), which consists of ten isozymes (a-j), is a lipid-metabolizing enzyme that phosphorylates DG to generate phosphatidic acid (PA) [6][7][8][9][10]. DG and PA are established lipid second messengers that regulate a wide variety of physiological and pathological events.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

Lü

Murakami

et al. 2020

FEBS Letters

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“…Given that ubiquitination is an essential post-translational modification that regulates GlyT2 expression and transport activity 14,24,25 and other neurotransmitter transporters [29][30][31]64 , we decided to explore whether this process is involved in the downregulation of GlyT2 by purmorphamine. We carried out established ubiquitination assays 24,65 in primary neurons treated 16 h with purmorphamine 10 µM or vehicle (Fig.…”

Section: Hedgehog Activation Downregulates Glyt2 Expression and Transmentioning

confidence: 99%

“…Ubiquitination, a post-translational modification in which the small protein ubiquitin is covalently attached to a cytoplasmic lysine residue of a protein, is a major control point that finely tunes the expression of GlyT2 14,17,24,25 . This mechanism is shared with other neurotransmitter transporters [26][27][28][29][30][31][32] although the E3 ubiquitin ligases involved in the process may differ in each case 24,33,34 .…”

Section: Introductionmentioning

confidence: 97%

The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo

Rocha-Munoz

Nunez

Gomez-Lopez

et al. 2020

Preprint

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The identity of a glycinergic synapse is maintained presynaptically by the activity of a surface glycine transporter, GlyT2, which recaptures glycine back to presynaptic terminals to preserve vesicular glycine content. GlyT2 loss-of-function mutations cause Hyperekplexia, a rare neurological disease in which loss of glycinergic neurotransmission causes generalized stiffness and strong motor alterations. However, the molecular underpinnings controlling GlyT2 activity remain poorly understood. In this work, we identify the Hedgehog pathway as a robust controller of GlyT2 expression and transport activity. Modulating the activation state of the Hedgehog pathway in vitro in rodent primary spinal cord neurons or in vivo in zebrafish embryos induced a selective control in GlyT2 expression, regulating GlyT2 transport activity. Our results indicate that activation of Hedgehog reduces GlyT2 expression by decreasing its mRNA levels and increasing its ubiquitination and degradation. This work describes a new molecular link between the Hedgehog signaling pathway and presynaptic glycine availability.

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Dopamine and the phosphorylated dopamine transporter are increased in the diacylglycerol kinase η‐knockout mouse brain

2021

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The molecular mechanisms generating the mania‐like abnormal behaviors caused by diacylglycerol (DG) kinase (DGK) η deficiency remain unclear. Here, we found that DGKη knockout markedly increased dopamine (DA) levels in the midbrain (DA‐producing region, 2.8‐fold) and cerebral cortex (DA projection region, 1.2‐fold). Moreover, DGKη deficiency significantly augmented phosphorylated DA transporter (DAT) levels (1.4‐fold increase), which induce DA efflux to the synaptic cleft, in the cerebral cortex. Moreover, phosphorylation levels of protein kinase C‐β, which is activated by DG and involved in DAT phosphorylation, were also increased. DAT expressed in Neuro‐2a cells recruited DGKη to the plasma membrane and colocalized with it. These results strongly suggest that dopaminergic hyperfunction caused by DGKη deficiency in the brain leads to mania‐like behaviors.

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Diacylglycerol kinase δ destabilizes serotonin transporter protein through the ubiquitin-proteasome system

Cited by 13 publications

References 41 publications

1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

1‐Stearoyl‐2‐docosahexaenoyl‐phosphatidic acid interacts with and activates Praja‐1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain

The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo

Dopamine and the phosphorylated dopamine transporter are increased in the diacylglycerol kinase η‐knockout mouse brain

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