Nerve growth factor-mediated inhibition of apoptosis post-caspase activation is due to removal of active caspase-3 in a lysosome-dependent manner.
Nerve growth factor (NGF) is well characterised as an important pro-survival factor in neuronal cells that can inhibit apoptotic cell death upstream of mitochondrial outer membrane permeabilisation. Here we addressed the question of whether NGF can also protect against apoptosis downstream of caspase activation. NGF treatment promoted a rapid reduction in the level of the p17 subunit of active caspase-3 in PC12 cells that had been induced to undergo apoptosis by various cytotoxins. The mechanism involved TrkA-dependent activation of extracellular signal-regulated kinase (ERK1/2) but not phosphatidylinositol 3-kinase (PI3K)/Akt, and de novo protein synthesis. Involvement of inhibitor of apoptosis proteins (IAPs) and proteasomal degradation were ruled out. In contrast, inhibition of lysosome function using chloroquine and concanamycin A reversed NGF-induced removal of p17. Moreover, in NGF-treated cells, active caspases were found to be localised to lysosomes. The involvement of macroautophagy and chaperone-mediated autophagy were ruled out. Taken together, these findings suggest an anti-apoptotic mechanism by which NGF induces removal of active caspase-3 in a lysosome-dependent manner.
1] Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland [2] Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
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Mnich
Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.
L A
LA
Carleton
Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.
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ET
Kavanagh
School of Medicine, National University of Ireland, Galway, Ireland.
K M
KM
Doyle
Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.
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0000000286108375
A
Samali
Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.
A M
AM
Gorman
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D055162:Biocatalysis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D051579:Neurogranin / Q000378:metabolism; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology
D018832:Molecular Chaperones; D051579:Neurogranin; D019284:Thapsigargin; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex