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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced mitochondrial pathway to apoptosis and caspase activation is potentiated by phospholipid scramblase-3

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Abstract

Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) initiate pathways of cell death in which caspase activation is mediated either directly (without mitochondrial amplification), or indirectly via the release of apoptogenic factors from mitochondria. Phospholipid scramblases (PLS) are enzymes that play a key role in cellular function by inducing bidirectional movement of membrane lipids. Changes in mitochondrial membrane lipids, cardiolipin, are critical for mediating apoptotic response in many cell-types. PLS3 is a phospholipid scramblase that is localized to mitochondria and is thought to be involved in the regulation of apoptotic signals. Here we report that exogenous-expression of PLS3 enhances apoptotic death induced by TRAIL. This is acheived by potentiating the mitochondrial arm of the death pathway. Thereby, PLS3 expression facilitates changes in mitochondrial membrane lipids that promote the release of apoptogenic factors and consequent full activation and processing of the caspase-9 and effector caspase-3. Moreover, we show that knock-down of endogenous PLS3 suppresses TRAIL-induced changes in cardiolipin. Finally, we demonstrate that TRAIL-induced activation of PKC-delta mediates regulation of the PLS3-induced changes in cardiolipin.

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Acknowledgements

We thank Drs. Wiedmer and Ohno for scramblase and PKCδ constructs, respectively. This work was supported by NIH grants CA105306 and HL080192 to RKF. RKF is an American Cancer Society Scholar. KN was supported by NIH 5 T32 HL07893 and UNCF/MERCK.

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Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Ave, Boston, MA, 02215, USA

    Kenneth Ndebele, Tai-Guang Jin, Nordine Benhaga, Anas Chalah & Roya Khosravi-Far

  2. Statistics and Consulting Unit, Department of Mathematics and Statistics, Boston University, 704 Commonwealth Ave, Boston, MA, 02215, USA

    Philimon Gona

  3. Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK

    Mauro Degli-Esposti

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  1. Kenneth Ndebele
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Correspondence to Roya Khosravi-Far.

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Ndebele, K., Gona, P., Jin, TG. et al. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced mitochondrial pathway to apoptosis and caspase activation is potentiated by phospholipid scramblase-3. Apoptosis 13, 845–856 (2008). https://doi.org/10.1007/s10495-008-0219-4

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