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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
Author(s) -
Lu Qiang,
Murakami Chiaki,
Murakami Yuki,
Hoshino Fumi,
Asami Maho,
Usuki Takako,
Sakai Hiromichi,
Sakane Fumio
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13765
Subject(s) - phosphatidic acid , ubiquitin ligase , diacylglycerol kinase , ubiquitin , serotonin , serotonergic , serotonin transporter , biology , microbiology and biotechnology , medicine , endocrinology , chemistry , phosphorylation , biochemistry , protein kinase c , receptor , phospholipid , membrane , gene
Serotonin 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) δ 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 DGKδ. 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 DGKδ‐knockout mouse brain, indicating that DGKδ 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 DGKδ activates Praja‐1 to degrade SERT in the brain.