Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair.
Rapid plasma membrane resealing is essential for cellular survival. Earlier studies showed that plasma membrane repair requires Ca(2+)-dependent exocytosis of lysosomes and a rapid form of endocytosis that removes membrane lesions. However, the functional relationship between lysosomal exocytosis and the rapid endocytosis that follows membrane injury is unknown. In this study, we show that the lysosomal enzyme acid sphingomyelinase (ASM) is released extracellularly when cells are wounded in the presence of Ca(2+). ASM-deficient cells, including human cells from Niemann-Pick type A (NPA) patients, undergo lysosomal exocytosis after wounding but are defective in injury-dependent endocytosis and plasma membrane repair. Exogenously added recombinant human ASM restores endocytosis and resealing in ASM-depleted cells, suggesting that conversion of plasma membrane sphingomyelin to ceramide by this lysosomal enzyme promotes lesion internalization. These findings reveal a molecular mechanism for restoration of plasma membrane integrity through exocytosis of lysosomes and identify defective plasma membrane repair as a possible component of the severe pathology observed in NPA patients.
Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
Christina
C
Tam
Vincent
V
Idone
Cecilia
C
Devlin
Maria Cecilia
MC
Fernandes
Andrew
A
Flannery
Xingxuan
X
He
Edward
E
Schuchman
Ira
I
Tabas
Norma W
NW
Andrews
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002518:Ceramides / Q000378:metabolism; D003891:Desipramine / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D008247:Lysosomes / Q000201:enzymology / Q000648:ultrastructure; D009542:Niemann-Pick Diseases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism
D002518:Ceramides; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase; D003891:Desipramine