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.
Perrotta
Cristiana
C
Unit of Clinical Pharmacology, Department of Clinical Sciences, University Hospital Luigi Sacco, Università degli Studi di Milano, 20157 Milan, Italy.
Bizzozero
Laura
L
Cazzato
Denise
D
Morlacchi
Sara
S
Assi
Emma
E
Simbari
Fabio
F
Zhang
Yang
Y
Gulbins
Erich
E
Bassi
Maria Teresa
MT
Rosa
Patrizia
P
Clementi
Emilio
E
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