MTMR4 regulates endosomal trafficking

Phosphatidylinositol 3-phosphate [PtdIns(3)P] regulates several aspects of the endocytic pathway, including receptor sorting from early endosomes. PtdIns(3)P is constitutively synthesized on early endosomes by the phosphoinositide 3-kinase complex hVps34–hVps15; however, the tight control of the cellular levels of PtdIns(3)P that is necessary for the regulation of endocytic trafficking must also involve a phosphoinositide 3-phosphatase. On page 3071, Christina Mitchell and colleagues identify MTMR4, a member of the myotubularin family of phosphoinositide 3-phosphatases, as this hitherto mysterious regulator of endocytic trafficking. They show that MTMR4 localizes to early endosomes and to Rab11-positive recycling endosomes in COS-1 cells. MTMR4 knockdown or expression of a catalytically inactive MTMR4 increases the number of PtdIns(3)P-decorated endosomes, they report, whereas MTMR4 overexpression delays the exit of the transferrin receptor from early endosomes and its recycling to the plasma membrane. Finally, they show that MTMR4 expression or knockdown also regulates the subcellular redistribution of Rab11 and VAMP3, two proteins that regulate the endocytic recycling compartment. Together, these results identify MTMR4 as a novel regulator of endosomal trafficking that localizes at the interface between early and recycling endosomes.