| First Author | Lu Q | Year | 2020 |
| Journal | Biochim Biophys Acta Mol Cell Biol Lipids | Volume | 1865 |
| Issue | 3 | Pages | 158608 |
| PubMed ID | 31891772 | Mgi Jnum | J:284261 |
| Mgi Id | MGI:6387115 | Doi | 10.1016/j.bbalip.2019.158608 |
| Citation | Lu Q, et al. (2020) Diacylglycerol kinase delta destabilizes serotonin transporter protein through the ubiquitin-proteasome system. Biochim Biophys Acta Mol Cell Biol Lipids 1865(3):158608 |
| abstractText | 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 DGKdelta-deficient brain. However, its molecular mechanisms remain unclear. We found that the catalytic subdomain-a and the coiled-coil structure-containing region of DGKdelta 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 DGKdelta in a catalytic activity-dependent manner. A proteasome inhibitor, MG-132, inhibited DGKdelta-dependent SERT degradation. Notably, DGKdelta 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 DGKdelta 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. |
