Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function.
Acid sphingomyelinase (A-SMase) is an important enzyme in sphingolipid metabolism and plays key roles in apoptosis, immunity, development, and cancer. In addition, it mediates cytotoxicity of cisplatin and some other chemotherapeutic drugs. The mechanism of A-SMase activation is still undefined. We now demonstrate that, upon CD95 stimulation, A-SMase is activated through translocation from intracellular compartments to the plasma membrane in an exocytic pathway requiring the t-SNARE protein syntaxin 4. Indeed, down-regulation of syntaxin 4 inhibits A-SMase translocation and activation induced by CD95 stimulation. This leads to inhibition of the CD95-triggered signaling events, including caspase 3 and 9 activation and apoptosis, activation of the survival pathway involving the protein kinase Akt, and important changes in cell cycle and proliferation. The molecular interaction between A-SMase and syntaxin 4 was not known and clarifies the mechanism of A-SMase activation. The novel actions of syntaxin 4 in sphingolipid metabolism and exocytosis we describe here define signaling mechanisms of broad relevance in cell pathophysiology.
Unit of Clinical Pharmacology, Department of Clinical Sciences, University Hospital Luigi Sacco, Università degli Studi di Milano, 20157 Milan, Italy.
Cristiana
C
Perrotta
Laura
L
Bizzozero
Denise
D
Cazzato
Sara
S
Morlacchi
Emma
E
Assi
Fabio
F
Simbari
Yang
Y
Zhang
Erich
E
Gulbins
Maria Teresa
MT
Bassi
Patrizia
P
Rosa
Emilio
E
Clementi
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D021381:Protein Transport / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism; D020298:U937 Cells; D019014:fas Receptor / Q000378:metabolism*
C491901:FAS protein, human; D050765:Qa-SNARE Proteins; D013109:Sphingomyelins; D019014:fas Receptor; D051057:Proto-Oncogene Proteins c-akt; D013108:Sphingomyelin Phosphodiesterase; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9