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Dead if You Do, Dead if You Don’t: How Caspase-8 Causes and Prevents Cell Death

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Necrotic Cell Death

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

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Abstract

The cell surface “death receptors” were named for their ability to activate caspase-8 and thereby trigger apoptotic cell death. Reports that activation of these receptors could nonetheless lead to cell death in the presence of caspase inhibitors were therefore surprising, as was the description of this latter form of death as “necrosis-like.” Of course, we now know that death receptor ligation in combination with caspase inhibition leads to activation of receptor-interacting protein kinase-1 (RIPK1) and RIPK3 and to necroptosis. Furthermore, biochemical and genetic studies have provided a mechanistic explanation for the effect of caspase inhibitors in this setting, by showing that the key initiator caspase of the extrinsic apoptotic pathway, caspase-8, is also required for cell survival because it suppresses RIPK-dependent necroptosis. This chapter will focus on the regulation of necroptosis by caspase-8 and on the functional links between the pathways of apoptosis and necroptosis. I will first briefly present these pathways and will then outline the current understanding of the mechanisms by which caspase-8 suppresses necroptosis. I will then discuss the implications of the functional links between apoptosis and necroptosis for determination of cell fate in vivo and speculate as to why these links may have been favored by mammalian evolution.

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  1. Department of Immunology, University of Washington, 750 Republican St., Seattle, WA, 98109, USA

    Andrew Oberst

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  1. Andrew Oberst
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Correspondence to Andrew Oberst .

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  1. Department of Physiology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore

    Han-Ming Shen

  2. Department of Biomedical Molecular Biology (UGent), VIB/University of Ghent Inflammation Research Center (VIB), Zwijnaarde, Belgium

    Peter Vandenabeele

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Oberst, A. (2014). Dead if You Do, Dead if You Don’t: How Caspase-8 Causes and Prevents Cell Death. In: Shen, HM., Vandenabeele, P. (eds) Necrotic Cell Death. Cell Death in Biology and Diseases. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-8220-8_6

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