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

AbstractSerotonin 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. Ho wever, 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 DG Kδ 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.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: RESEARCH LETTER Source Type: research