Ubiquitin-specific peptidase 11 selectively interacts with and deubiquitination-dependently stabilizes diacylglycerol kinase δ to maintain cellular glucose uptake.

Abstract

Diacylglycerol kinase δ (DGKδ) phosphorylates diacylglycerol and converts it into phosphatidic acid. DGKδ contributes to glucose uptake as one of its cellular functions. However, detail mechanisms underlying the regulation of DGKδ protein stability remain unelucidated. Herein, we identified ubiquitin-specific peptidase 11 (USP11) in the DGKδ protein complex by DGKδ-interactome analysis. By mapping analysis, we clarified that a wider region of USP11, including the catalytic domain 1 region, and both the C1 domains and catalytic subdomain-a of DGKδ mainly contributed to their association. Cellular dysfunction of USP11 by mitoxiantrone (a USP11-specific inhibitor) or siRNA knockdown markedly decreased DGKδ protein levels. Additionally, we found that DGKδ ubiquitination was increased by USP11 dysfunction, and cumulative ubiquitination was reduced by rescue manipulation. Functionally, USP11 dysfunction reduced cellular glucose uptake. Altogether, our findings provide the first evidence that USP11 deubiquitination-dependently stabilizes DGKδ to maintain cellular glucose uptake.