A phosphoinositide conversion mechanism for exit from endosomes

A mechanism for phosphoinositide conversion at endosomes to enable exit from the endosomal system, suggesting that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy. Phosphoinositide conversion during endosome exit Directional membrane traffic requires regulated conversion of phosphoinositides (PIs) — membrane phospholipids that act as determinants of membrane identity — by PI metabolizing enzymes. Volker Haucke and co-workers studied the mechanism of PI identity shifts during trafficking from the endosomal system — defined by phosphatidylinositol 3-phosphate (PI(3)P) — to the secretory compartments and the plasma membrane, dominated by phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ). The authors find that endosomal cargo en route to intracellular destinations can change direction and make its way back to the cell surface by the action of two enzymes. Specifically, PI(3)P on the membrane of these compartments is hydrolysed by the phosphatase MTM1, an enzyme whose loss of function leads to X-linked centronuclear myopathy in humans. This hydrolysis of PI(3)P is accompanied by the generation of PI(4)P through the action of phosphatidylinositol 4-kinase, as well as the recruitment of the exocyst tethering complex to enable subsequent membrane fusion. Phosphoinositides are a minor class of short-lived membrane phospholipids that serve crucial functions in cell physiology ranging from cell signalling and motility to their role as signposts of compartmental membrane identity 1 , 2 . Phosphoinositide 4-phosphates such as phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) are concentrated at the plasma membrane, on secretory organelles 3 , and on lysosomes 4 , whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P) 5 , are a hallmark of the endosomal system 1 , 2 . Directional membrane traffic between endosomal and secretory compartments, although inherently complex, therefore requires regulated phosphoinositide conversion. The molecular mechanism underlying this conversion of phosphoinositide identity during cargo exit from endosomes by exocytosis is unknown. Here we report that surface delivery of endosomal cargo requires hydrolysis of PI(3)P by the phosphatidylinositol 3-phosphatase MTM1, an enzyme whose loss of function leads to X-linked centronuclear myopathy (also called myotubular my