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-Mase is activated through translocation from intracellular compartments to the plasma membrane in an exocytic pathway requiring the t-SNARE protein syntaxin 4. Indeed, downregulation 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.
Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function / C. Perrotta, L. Bizzozero, D. Cazzato, S. Morlacchi, E. Assi, F. Simbari, Y. Zhang, E. Gulbins, M. T. Bassi, P. Rosa, E.G.I. Clementi. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 285:51(2010), pp. 40240-40251.
|Titolo:||Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore BIO/10 - Biochimica
Settore BIO/13 - Biologia Applicata
|Data di pubblicazione:||2010|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1074/jbc.M110.139287|
|Appare nelle tipologie:||01 - Articolo su periodico|