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

Brain-specific diacylglycerol kinase (DGK) ?-knockout mice exhibited serotonin transporter (SERT) inhibitor-sensitive obsessive-compulsive disorder-like behaviors. Moreover, SERT protein levels were markedly increased in the DGK?-deficient brain. However, its molecular mechanisms remain unclear. We found that the catalytic subdomain-a and the coiled-coil structure-containing region of DGK? interacted with the C-terminal cytoplasmic region ...
(CTC) of SERT. Moreover, the protein levels of full-length SERT and SERT-CTC alone were significantly decreased by DGK? in a catalytic activity-dependent manner. A proteasome inhibitor, MG-132, inhibited DGK?-dependent SERT degradation. Notably, DGK? 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? 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 obsessive-compulsive disorder, depression, autism and schizophrenia.
Mesh Terms:
Animals, COS Cells, Chlorocebus aethiops, Diacylglycerol Kinase, Male, Mice, Mice, Inbred C57BL, Proteasome Endopeptidase Complex, Protein Binding, Proteolysis, Serotonin Plasma Membrane Transport Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Biochim Biophys Acta Mol Cell Biol Lipids
Date: Dec. 01, 2019
Download Curated Data For This Publication
227258
Switch View:
  • Interactions 10