TY - JOUR
T1 - A phosphoinositide conversion mechanism for exit from endosomes
AU - Ketel, Katharina
AU - Krauss, Michael
AU - Nicot, Anne Sophie
AU - Puchkov, Dmytro
AU - Wieffer, Marnix
AU - Müller, Rainer
AU - Subramanian, Devaraj
AU - Schultz, Carsten
AU - Laporte, Jocelyn
AU - Haucke, Volker
N1 - Funding Information:
Acknowledgements We thank L. Pluska for initial studies on PI4K2α-exocyst, I. Ganley for fluorescently labelled p40-Phox, M. Ringling, M. Mühlbauer, L. von Oertzen, and S. Zillmann for technical assistance, and A. Marat for comments. This work was supported by grants from the German Research Foundation (SFB740/C8 to V.H. and SFB958/A11 to M.K.) and Agence Nationale de la Recherche (ANR-14-CE12-0009/13-BSV2-0004 to J.L.).
Publisher Copyright:
© 2014 Macmillan Publishers Limited.
PY - 2016/1/21
Y1 - 2016/1/21
N2 - 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. 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, and on lysosomes, whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P), are a hallmark of the endosomal system. 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 myopathy) in humans. Removal of endosomal PI(3)P by MTM1 is accompanied by phosphatidylinositol 4-kinase-2α (PI4K2α)-dependent generation of PI(4)P and recruitment of the exocyst tethering complex to enable membrane fusion. Our data establish a mechanism for phosphoinositide conversion from PI(3)P to PI(4)P at endosomes en route to the plasma membrane and suggest that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by mutation of MTM1 in humans.
AB - 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. 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, and on lysosomes, whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P), are a hallmark of the endosomal system. 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 myopathy) in humans. Removal of endosomal PI(3)P by MTM1 is accompanied by phosphatidylinositol 4-kinase-2α (PI4K2α)-dependent generation of PI(4)P and recruitment of the exocyst tethering complex to enable membrane fusion. Our data establish a mechanism for phosphoinositide conversion from PI(3)P to PI(4)P at endosomes en route to the plasma membrane and suggest that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by mutation of MTM1 in humans.
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U2 - 10.1038/nature16516
DO - 10.1038/nature16516
M3 - Article
C2 - 26760201
AN - SCOPUS:84955323578
VL - 529
SP - 408
EP - 412
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7586
ER -