Acetylation suppresses the proapoptotic activity of GD3 ganglioside.
GD3 synthase is rapidly activated in different cell types after specific apoptotic stimuli. De novo synthesized GD3 accumulates and contributes to the apoptotic program by relocating to mitochondrial membranes and inducing the release of apoptogenic factors. We found that sialic acid acetylation suppresses the proapoptotic activity of GD3. In fact, unlike GD3, 9-O-acetyl-GD3 is completely ineffective in inducing cytochrome c release and caspase-9 activation on isolated mitochondria and fails to induce the collapse of mitochondrial transmembrane potential and cellular apoptosis. Moreover, cells which are resistant to the overexpression of the GD3 synthase, actively convert de novo synthesized GD3 to 9-O-acetyl-GD3. The coexpression of GD3 synthase with a viral 9-O-acetyl esterase, which prevents 9-O-acetyl-GD3 accumulation, reconstitutes GD3 responsiveness and apoptosis. Finally, the expression of the 9-O-acetyl esterase is sufficient to induce apoptosis of glioblastomas which express high levels of 9-O-acetyl-GD3. Thus, sialic acid acetylation critically controls the proapoptotic activity of GD3.
Malisan
Florence
F
Laboratory of Immunology and Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy.
Franchi
Luigi
L
Tomassini
Barbara
B
Ventura
Natascia
N
Condò
Ivano
I
Rippo
Maria Rita
MR
Rufini
Alessandra
A
Liberati
Laura
L
Nachtigall
Claudia
C
Kniep
Bernhard
B
Testi
Roberto
R
D000107:Acetylation; D000115:Acetylesterase / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D005434:Flow Cytometry; D005732:Gangliosides / Q000737:chemistry / Q000378:metabolism*; D006028:Glycosphingolipids / Q000737:chemistry / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019158:N-Acetylneuraminic Acid / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism
D005732:Gangliosides; D006028:Glycosphingolipids; D011956:Receptors, Cell Surface; C026226:ganglioside, GD3; D000115:Acetylesterase; D020169:Caspases; D019158:N-Acetylneuraminic Acid