Hereditary Spastic Paraplegia Protein Spartin Is an FK506-Binding Protein Identified by mRNA Display

• Spartin is identified as a FK506-binding protein by using mRNA display
• FK506 inhibits interaction of spartin with lipid droplet-associated protein, TIP47
• FK506 blocks colocalization of spartin and an E3 ligase AIP4 in lipid droplets
• FK506 increases the protein level of ADRP, a regulator of lipid homeostasis

SummaryHere, we used mRNA display to search for proteins that bind to FK506, a potent immunosuppressant drug, and identified spartin, a hereditary spastic paraplegia protein, from a human brain cDNA library. We demonstrated that FK506 binds to the C-terminal region of spartin and thereby inhibits the interaction of spartin with TIP47, one of the lipid droplet-associated proteins. We further confirmed that FK506 inhibits localization of spartin and its binder, an E3 ubiquitin ligase AIP4, in lipid droplets and increases the protein level of ADRP (adipose differentiation-related protein), which is a regulator of lipid homeostasis. These results strongly suggest that FK506 suppresses the proteasomal degradation of ADRP, a substrate of AIP4, by inhibiting the spartin-TIP47 interaction and thereby blocking the localization of spartin and AIP4 in lipid droplets.

Graphical AbstractFigure optionsDownload high-quality image (197 K)Download as PowerPoint slide