Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1865, Issue 3, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbalip.2019.158608
Keywords
Diacylglycerol kinase; Serotonin transporter; Praja-1; Melanoma antigen gene-D1; Obsessive-compulsive disorder
Funding
- MEXT/JSPS [KAKENHI] [26291017, 15K14470, 17H03650]
- Futaba Electronics Memorial Foundation
- Ono Medical Research Foundation
- Japan Foundation for Applied Enzymology
- Food Science Institute Foundation
- Skylark Food Science Institute
- Asahi Group Foundation
- Japan Milk Academic Alliance
- Japan Food Chemical Research Foundation
- SENSHIN Medical Research Foundation
- Grants-in-Aid for Scientific Research [17H03650] Funding Source: KAKEN
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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.
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