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

Brain-specific diacylglycerol kinase (DGK) delta-knockout mice exhibited serotonin transporter (SERT) inhibitor-sensitive obsessive-compulsive disorder-like behaviors. Moreover, SERT protein levels were markedly increased in the DGK delta-deficient brain. However, its molecular mechanisms remain unclear. We found that the catalytic subdomain-a and the coiled-coil structure-containing region of DGK delta interacted with the C-terminal cytoplasmic region (CTC) of SERI. Moreover, the protein levels of full-length SERT and SERT-CTC alone were significantly decreased by DGK delta in a catalytic activity-dependent manner. A proteasome inhibitor, MG-132, inhibited DGK delta-dependent SERT degradation. Notably, DGK delta interacted with MAGE-D1 adaptor protein and Praja-1 E3 ubiquitin-protein ligase, and enhanced the ubiquitination of SERT through Praja-1. Taken together, these results indicate that DGK delta interacts with SERT and induces SERT degradation in an activity-dependent manner through the Praja-1 ubiquitin ligase-proteasome system. These new findings provide novel insights into serotonergic system regulation and the pathophysiology/therapeutics of serotonin-/SERT-related diseases such as obsessivecompulsive disorder, depression, autism and schizophrenia.