Necroptosis as an alternative form of programmed cell death

Christofferson, Dana E.; Yuan, Junying

doi:10.1016/j.ceb.2009.12.003

Cited by 696 publications

(576 citation statements)

References 35 publications

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“…Rupture of the mitochondrial outer membrane releases all of the accumulated Ca 2+ and ROS, as well as numerous pro-apoptotic proteins (e.g., cytochrome c, apoptosis-inducing factor, SMAC/Diablo, and endonuclease-G) into the cytosol. Together, these substances can contribute to several forms of programmed cell death (i.e, any form of cell death mediated by intracellular machinery) including apoptosis, necroptosis, and autophagy [34][35][36][37][38]. However, activation and spread of these pathways is dependent on energy (ATP).…”

Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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Summary: Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A "systems approach" at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.

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Section: Mitochondrial Permeability Transition Porementioning

confidence: 99%

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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“…This simple paradigm has been challenged by findings that necrosis can be the result of programmed signaling. 6,7 Programmed necrosis (necroptosis) can be specifically blocked by necrostatin-1 (Nec-1), a small-molecule inhibitor of the kinase activity of receptor interacting protein 1 (Rip1). 8 Necroptosis is generally regarded as an alternative death pathway, activated when caspase-mediated death is inhibited.…”

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confidence: 99%

cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

et al. 2012

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Cellular inhibitor of apoptosis proteins (cIAPs) have emerged as important anti-cell death mediators, particularly in cancer. Although they are known to be expressed in immune tissue, their specific immune function remains unclear. We observed that degradation of cIAPs with SMAC mimetic (SM) results in death of primary bone-marrow-derived macrophages. SM-induced death of macrophages occurred by programmed necrosis (necroptosis), which was dependent on TNF receptor expression. Consistent with necroptosis, SM-induced death of macrophages was abrogated by inhibition of receptor interacting protein 1 (Rip1) kinase signaling or by receptor interacting protein 3 (Rip3) knockdown. SM-induced necroptosis was also dependent on inhibition of SM-induced apoptosis due to the expression of the endogenous caspase inhibitor, xIAP. We found that cIAPs limit Rip3, and to a lesser extent Rip1, expression via post-transcriptional mechanisms, leading to inhibition of the Rip1-Rip3 death complex (necrosome). Reduced cIAP activity in vivo, via SM treatment or specific knockout of either cIAP, resulted in elevated macrophage cell death and compromised control of an intracellular bacterium, Listeria monocytogenes. These results show that cIAPs have an important role in limiting programmed necrosis of macrophages, which facilitates effective control of a pathogen.

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“…These results demonstrate that, similar to the expression of Fas, the presence of RIP maintains the preference of apoptosis over necrosis in CSup-mediated cell death. They demonstrate the unique and essential role of RIP in CSup-induced apoptosis, which is distinct from the common role of RIP as a crucial player in necrosis or necroptosis that can occur with or without death receptor activation (48,49).…”

Section: Rip Is Required For Csup-induced But Not For Classical Fas-mmentioning

confidence: 99%

Vesicles Released by Activated T Cells Induce Both Fas-Mediated RIP-Dependent Apoptotic and Fas-Independent Nonapoptotic Cell Deaths

Koncz

Hancz

Chakrabandhu

et al. 2012

The Journal of Immunology

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Activated T cells secrete Fas ligand (FasL)-containing vesicles (secreted vesicles) that induce death of target cells. We provide evidence that secreted vesicles from culture supernatants (Csup) of various origins are able to generate both Fas-dependent apoptotic and Fas-independent, nonapoptotic cell death. In the absence of Fas, the nonapoptotic, Fas-independent pathway could still induce cell death. In contrast to RIP-independent classical Fas-induced cell death triggered by cross-linked or membrane-bound FasL, CSup-derived stimuli-induced apoptosis exhibited unique molecular and enzymatic characteristics. It could be partially inhibited by blocking cathepsin D enzyme activity and required the presence of RIP. Whereas stimulation with CSup, derived from both FasL-overexpressing Jurkat cells and PBMC, could induce cell death, the requirements for Fas-associated death domain protein and caspase-9 were different between the two systems. Our study highlights an important distinction between cell contact-mediated and secreted vesicle-generated activation-induced cell death and also demonstrates that the type of the secreted vesicles can also modify the cell death route. We propose that besides cell-to-cell interaction-mediated Fas triggering, stimuli induced by secreted vesicles can mediate important additional cell death signals regulating activation-induced cell death under physiological conditions.

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Necroptosis as an alternative form of programmed cell death

Cited by 696 publications

References 35 publications

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

Vesicles Released by Activated T Cells Induce Both Fas-Mediated RIP-Dependent Apoptotic and Fas-Independent Nonapoptotic Cell Deaths

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