Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule

Holler, Nils; Zaru, Rossana; Micheau, Olivier; Thome, Margot; Attinger, Antoine; Valitutti, Salvatore; Bodmer, Jean-Luc; Schneider, Pascal; Seed, Brian; Tschopp, Jürg

doi:10.1038/82732

Cited by 1,706 publications

(1,583 citation statements)

References 36 publications

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“…13,14,32 Moreover, we wanted to examine which caspases have essential functions to induce apoptosis by CD8 T cells using caspase inhibitors. CTL from C57BL/6 and B6-PKO mice immunized with irradiated 39.5-B7 cells were tested in 18 hour assays, in the presence and absence of the broad caspase inhibitors, z-VAD-fmk (50 mM) and inhibitors of caspase-8 (z-IETDfmk, 50 mM) or caspase-9 (z-LEHD-fmk, 50 mM) (Fig 8).…”

Section: Caspase-dependent Apoptosis In Tumor Cellsmentioning

confidence: 99%

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

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Perforin/granzyme B-and Fas/FasL-mediated killing pathways are the main effector mechanisms of CTL and NK cells in antitumor immune responses. In this study, we investigated the relative role of these two lytic mechanisms in protection of the host from tumor progression, as well as spontaneous metastasis, using the D122 Lewis lung carcinoma and its gene-modified cells. Utilizing perforin knockout mice (B6-PKO) and Fas and FasL mutant (B6-MRL and B6-Smn) mice, we found that perforin expression in the host plays a crucial function in the prevention of metastasis. However, local tumor rejection of an H-2K b and B7-1 transfectant, 39.5-B7 cells, was not dependent either on perforin or Fas/FasL expression in vivo. In addition, CTL lysis of 39.5-B7 cells was independent of perforin and Fas/FasL interactions in 18-hour in vitro assays. We also confirmed that CD8 T-cells were responsible for rejecting 39.5-B7 local tumors, yet cytokines, TNF-a and gIFN were not involved in tumor rejection in vivo. Furthermore, blocking assays using caspase inhibitors (zVAD-fmk, zIETD-fmk and zLEHD-fmk) showed that, whereas caspase activation was partially required to induce 39.5-B7 lysis mediated by the perforin-dependent pathway, 39.5-B7 lysis by CTLs through the perforin-independent mechanism required caspase activation. Thus, these results suggested that perforin, Fas/FasL, gIFN and TNF-a independent lytic mechanisms, mediated by CD8 T cells, have a crucial role in rejection of 39.5-B7 cells in vivo. Caspase activation is a pre requisite for apoptosis of targets by CTLs

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Section: Caspase-dependent Apoptosis In Tumor Cellsmentioning

confidence: 99%

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

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“…Engagement of the death receptor leads to the recruitment of the adaptor protein FADD, which in turn can recruit and activate caspase-8 (then leading to apoptosis) or RIP1 ( Figure 1). Depending on cells, conditions and stimuli, inhibition of caspase-8 can truly interrupt lethal signaling, favor a switch from apoptotic to necrotic cell death, [17][18][19] which depends on RIP1, 20,21 or induce (again RIP1-dependent) autophagic cell death. 22 Caspase inhibition has also been shown to lead to a switch from apoptosis to necrosis in, for example, thymocytes responding to DNA damage 23 or from apoptosis to autophagic cell death in, for example, growth factor-deprived neurons.…”

Section: Inhibition/replacement Of Cell Death Typesmentioning

confidence: 99%

Redundant cell death mechanisms as relics and backups

Golstein

Kroemer

2005

Cell Death Differ

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Here we review recent observations indicating the existence of redundant cell death mechanisms. We speculate that this redundancy reflects a particular evolutionary history for cellular demise. Autophagic or apoptotic elements might have been added to a primordial death mechanism, initially improving cell dismantling and later acquiring the ability to act themselves as death effectors. The resulting redundancy of cell death mechanisms has pathophysiological implications.

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“…[21][22][23] Therefore, we used RIP1-deficient (RIP À ) Jurkat cells to study the involvement of the protein in dsRNA-induced apoptosis and necrosis. When we treated RIP1 À Jurkat cells with IFN þ dsRNA, in the presence or absence of zVAD-fmk, they failed to respond by necrosis or apoptosis in contrast to parental (RIP1 þ ) cells (Figure 2a Similar to RIP1 most of the cellular PKR is probably not a monomer and may be included in protein complexes.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed during the early stages of apoptosis, both RIP1 and PKR are cleaved, whereas RIP1 is eliminated and PKR is activated. RIP1 cleavage leads to inhibition of NF-kB activation and prevents necrosis, 21,22,28 whereas PKR cleavage inhibits de novo protein production and promotes apoptosis. 16 Therefore, cleavage of PKR and RIP1 may act to promote apoptosis while decreasing inflammatory signaling and necrosis.…”

Section: Discussionmentioning

confidence: 99%

The caspase-generated fragments of PKR cooperate to activate full-length PKR and inhibit translation

Kalai¹,

Suin²,

Festjens³

et al. 2007

Cell Death Differ

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We have studied the involvement of receptor interacting protein kinase-1 (RIP1) and dsRNA-activated protein kinase (PKR) in external dsRNA-induced apoptotic and necrotic cell death in Jurkat T cell lymphoma. Our results suggest that RIP1 plays an imported role in dsRNA-induced apoptosis and necrosis. We demonstrated that contrary to necrosis, protein synthesis is inhibited in apoptosis. Here, we show that phosphorylation of translation initiation factor 2-a (eukaryotic initiation factor 2-a (eIF2-a)) and its kinase, PKR, occur in dsRNA-induced apoptosis but not in necrosis. These events are caspase-dependent and coincide with the appearance of the caspase-mediated PKR fragments, N-terminal domain (ND) and kinase domain (KD). Our immunoprecipitation experiments demonstrated that both fragments could independently co-precipitate with full-length PKR. Expression of PKR-KD leads to PKR and eIF2-a phosphorylation and inhibits protein translation, whereas that of PKR-ND does not. Co-expression of PKR-ND and PKR-KD promotes their interaction with PKR, PKR and eIF2-a phosphorylation and suppresses protein translation better than PKR-KD alone. Our findings suggest a caspase-dependent mode of activation of PKR in apoptosis in which the PKR-KD fragment interacts with and activates intact PKR. PKR-ND facilitates the interaction of PKR-KD with full-length PKR and thus the activation of the kinase and amplifies the translation inhibitory signal.

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Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule

Cited by 1,706 publications

References 36 publications

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

Redundant cell death mechanisms as relics and backups

The caspase-generated fragments of PKR cooperate to activate full-length PKR and inhibit translation

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