Human myotubularin-related protein 9 regulates ER-to-Golgi trafficking and modulates WNT3A secretion.

Regulation of phosphatidylinositol phosphates plays a crucial role in signal transduction, membrane trafficking or autophagy. Members of the myotubularin family of lipid phosphatases contribute to phosphoinositide metabolism by counteracting the activity of phosphoinositide kinases. The mechanisms determining their subcellular localization and targeting to specific membrane compartments are still poorly understood. We show here that the inactive phosphatase MTMR9 localizes to the intermediate compartment and to the Golgi apparatus and is able to recruit its active phosphatase partners MTMR6 and MTMR8 to these locations. Furthermore, MTMR8 and MTMR9 co-localize with the small GTPase RAB1A and regulate its localization. Loss of MTMR9 expression compromises the integrity of the Golgi apparatus and results in altered distribution of RAB1A and actin nucleation-promoting factor WHAMM. Loss or overexpression of MTMR9 leads to decreased rate of protein secretion. We demonstrate that secretion of physiologically relevant cargo exemplified by the WNT3A protein is affected after perturbation of MTMR9 levels.