DTBC22Regulates Lysosomal Membrane Protein Trafficking Through Rab40

Proteins will be transported to the specific destinations through vesicular trafficking after they are synthesized. The correct delivery of proteins is critical to the maintenance of the cellular morphology and function. Vesicular trafficking defects cause varieties of human disease.Lysosome is a central degradation organelle in the eukaryotic cells to digest cellular wastes and recycle nutrients. Malfunction of lysosome results in multiple developmental disorders and human diseases. Spinster (Spin) is a late endosomal/lysosomal membrane protein with homology to a sugar carrier. LAMP is a lysosome associated membrane protein that is essential for the enzyme activities in lysosome.In a forward genetic screen, we identified a novel essential gene named dTBC22encoding a Tre2-Bub2-Cdcl6(TBC) domain containing protein that is required for proper trafficking of Spinster and LAMP. dTBC22interacts with small GTPase Rab40and has Rab40GTPase-activating protein (GAP) activity. dTBC22deficiency changes subcellular localization of Rab40. The trafficking of Spinster is affected when an active form of Rab40(Rab40CA) was overexpressed. Rab40is mainly localized on Golgi apparatus and its SOCS domain, the Cullin binding motif LPLP, is required for Rab40localized on Golgi. The morphology of Golgi is changed and Spin is accumulated in Golgi in both dTBC22mutant clones and in Rab40CA overexpressed tissues. Above all, we found a new gene dTBC22encodes a protein that could regulate the trafficking of lysosomal membrane protein through Rab40.