PARP1-mediated necrosis is dependent on parallel JNK and Ca²⁺/calpain pathways.
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| Abstract |
Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme that can trigger caspase-independent necrosis. Two main mechanisms for this have been proposed: one involving RIP1 and JNK kinases and mitochondrial permeability transition (MPT), the other involving calpain-mediated activation of Bax and mitochondrial release of apoptosis-inducing factor (AIF). However, whether these two mechanisms represent distinct pathways for PARP1-induced necrosis, or whether they are simply different components of the same pathway has yet to be tested. Mouse embryonic fibroblasts (MEFs) were treated with either N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or β-Lapachone, resulting in PARP1-dependent necrosis. This was associated with increases in calpain activity, JNK activation and AIF translocation. JNK inhibition significantly reduced MNNG- and β-Lapachone-induced JNK activation, AIF translocation, and necrosis, but not calpain activation. In contrast, inhibition of calpain either by Ca(2+) chelation or knockdown attenuated necrosis, but did not affect JNK activation or AIF translocation. To our surprise, genetic and/or pharmacological inhibition of RIP1, AIF, Bax and the MPT pore failed to abrogate MNNG- and β-Lapachone-induced necrosis. In conclusion, although JNK and calpain both contribute to PARP1-induced necrosis, they do so via parallel mechanisms.
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| Authors | Diana L Douglas, Christopher P Baines |
| Journal | Journal of cell science (J Cell Sci) Vol. 127 Issue Pt 19 Pg. 4134-45 (Oct 01 2014) ISSN: 1477-9137 [Electronic] England |
| PMID | 25052090 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
| Copyright | © 2014. Published by The Company of Biologists Ltd. |
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