Activation of the NF-κB pathway by Caspase 8 and its homologs

Chaudhary, Preet M.; Eby, Michael T.; Jasmin, Alan; Kumar, Arvind; Liu, Li; Hood, Leroy

doi:10.1038/sj.onc.1203812

Cited by 222 publications

(208 citation statements)

References 45 publications

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“…14,17 To test this we examined degradation of IkB in response to TNF. WT, caspase-8 À/À , and FLIP À/À MEFs were treated with TNF for various time periods and IkB levels were determined by western blotting.…”

Section: Resultsmentioning

confidence: 99%

“…[15][16][17] It has been reported that FLIP and caspase-8 are sometimes necessary for activation of NF-kB, or are capable of activating NF-kB when overexpressed. 13,14 For example, Hu et al 13 found that overexpression of FLIP or caspase-8 caused potent activation of an NF-kB reporter in 293HEK cells, and Chaudhary et al 14 found that overexpression of caspase-8 or FLIP in 293T or MCF7 cells activated NF-kB reporters. Interestingly, both groups found that, although catalytically inactive forms of caspase-8 were still able to induce NF-kB, and neither viral nor synthetic caspase inhibitors could block this, these inhibitors were able to block NF-kB induction by overexpression of FLIP, suggesting that proteolysis of FLIP by caspase-8 is not required for it to activate NF-kB, but might be necessary for caspase-8 to somehow activate FLIP.…”

mentioning

confidence: 99%

“…For example, whereas activation of caspase-8 can cause apoptosis of many cell types, in others, such as T-lineage cells and hematopoietic progenitor cells, caspase-8 has been reported to act upstream, and was required for activation of NF-kB or for cellular proliferation. [11][12][13][14] In human Jurkat T cells, FLIP has also been reported to activate NF-kB, and thereby to inhibit caspase-8-induced cell death. [15][16][17] It has been reported that FLIP and caspase-8 are sometimes necessary for activation of NF-kB, or are capable of activating NF-kB when overexpressed.…”

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In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

et al. 2011

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Binding of TNF to TNF receptor-1 can give a pro-survival signal through activation of p65/RelA NF-jB, but also signals cell death. To determine the roles of FLICE-inhibitory protein (FLIP) and caspase-8 in TNF-induced activation of NF-jB and apoptosis, we used mouse embryonic fibroblasts derived from FLIP and caspase-8 gene-deleted mice, and treated them with TNF and a smac-mimetic compound that causes degradation of cellular inhibitor of apoptosis proteins (cIAPs). In cells treated with smac mimetic, TNF and Fas Ligand caused wild-type and FLIP À/À MEFs to die, whereas caspase-8 À/À MEFs survived, indicating that caspase-8 is necessary for death of MEFs triggered by these ligands when IAPs are degraded. By contrast, neither caspase-8 nor FLIP was required for TNF to activate p65/RelA NF-jB, because IjB was degraded, p65 translocated to the nucleus, and an NF-jB reporter gene activated normally in caspase-8 À/À or FLIP À/À MEFs. Reconstitution of FLIP À/À MEFs with the FLIP isoforms FLIP-L, FLIP-R, or FLIP-p43 protected these cells from dying when treated with TNF or FasL, whether or not cIAPs were depleted. These results show that in MEFs, caspase-8 is necessary for TNF-and FasL-induced death, and FLIP is needed to prevent it, but neither caspase-8 nor FLIP is required for TNF to activate NF-jB. Ligation of members of the TNF receptor superfamily typically triggers activation of transcription factors such as NF-kB, as well as proteins that can lead to cell death, such as RIPK1 and caspase-8. 1,2 The regulatory pathways that culminate in a pro-survival or apoptosis signal depend on the specific receptor that is ligated and the actions of proteins that transduce and modulate the signals flowing from it. For example, cellular inhibitor of apoptosis proteins (cIAP1 and cIAP2) and TNF receptor-associated factors (TRAF2 and TRAF3) are needed to prevent apoptosis of cells exposed to TNF, and favor activation of canonical (p65/RelA) NF-kB versus non-canonical (p100) NF-kB2. [3][4][5] Although TNF alone does not kill wild-type (WT) MEFs, it does cause apoptosis of MEFs in which genes for TRAF2 or p65/RelA NF-kB are deleted. 6 TNF can also kill MEFs that are mutant for cIAP1, and those in which cIAPs are depleted owing to treatment with a synthetic IAP antagonist 'smac-mimetic' compound. 7 These experiments indicate that pathways requiring cIAPs, TRAF2, and p65/RelA are normally able to block TNF-induced pro-apoptotic signals. Because treatment of cells with the translational inhibitor cycloheximide also sensitizes MEFs to killing by TNF, these experiments suggest that NF-kB drives the expression of cell death-inhibitory genes. 8 One of the NF-kB-regulated genes that is proposed to inhibit TNF-induced apoptosis is FLICE-inhibitory protein (FLIP). FLIP is structurally related to caspase-8. Like caspase-8, FLIP's N-terminus contains two death effector domains (DEDs), and its C-terminus has a caspase-like domain that is proteolytically inactive. 9 Transcripts from the murine FLIP gene can undergo alternative splicing to pro...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

et al. 2011

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“…c-FLIP L , which resembles caspase-8 albeit lacking the proteolytically active cysteine in the caspase homology domain, is able to participate in autoprocessing and membranerestricted activation of caspase-8 (29 -32). c-FLIP L can also be cleaved by caspase-8, and the cleaved p43 form of c-FLIP L has been suggested to promote NF-B signaling (33)(34)(35)(36)(37)(38). In contrast, c-FLIP S , which lacks the caspase homology domain, inhibits binding and oligomerization of caspase-8 in the DISC, thereby preventing the activating cleavage of caspase-8 (29) and generation of the cleaved NF-B-activating fragment of c-FLIP L .…”

Section: Fever-like Hyperthermia Controls T Lymphocyte Persistence Bymentioning

confidence: 99%

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Meinander

Söderström

Kaunisto

et al. 2007

The Journal of Immunology

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Fever has a major impact on immune responses by modulating survival, proliferation, and endurance of lymphocytes. Lymphocyte persistence in turn is determined by the equilibrium between death and survival-promoting factors that regulate death receptor signaling in these cells. A potential integrator of death receptor signaling is the caspase-8 inhibitor c-FLIP, the expression of which is dynamically regulated, either rapidly induced or down-regulated. In this study, we show in activated primary human T lymphocytes that hyperthermia corresponding to fever triggered down-regulation of both c-FLIP-splicing variants, c-FLIPshort (c-FLIPS) and c-FLIPlong, with consequent sensitization to apoptosis mediated by CD95 (Fas/APO-1). The c-FLIP down-regulation and subsequent sensitization was specific for hyperthermic stress. Additionally, we show that the hyperthermia-mediated down-regulation was due to increased ubiquitination and proteasomal degradation of c-FLIPS, the stability of which we have shown to be regulated by its C-terminal splicing tail. Furthermore, the induced sensitivity to CD95 ligation was independent of heat shock protein 70, as thermotolerant cells, expressing substantially elevated levels of heat shock protein 70, were not rescued from the effect of hyperthermia-mediated c-FLIP down-regulation. Our findings indicate that fever significantly influences the rate of lymphocyte elimination through depletion of c-FLIPS. Such a general regulatory mechanism for lymphocyte removal has broad ramifications for fever-mediated regulation of immune responses.

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“…Functional inactivation of the adaptor protein FADD leads to defective T and B cell proliferation in mice [12,[16][17][18]. Such a proliferative rather than apoptotic pathway might originate from an activated death receptor like CD95 and may be transmitted through FADD and c-FLIP, leading to the activation of the NF-jB and Erk transcriptional pathways [19][20][21][22]. This model is supported by transgenic mice that overexpress FLIP L in T cells [23].…”

Section: Introductionmentioning

confidence: 96%

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

et al. 2005

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The cellular homologues of the viral anti-apoptotic v-FLIP proteins exist as a long (c-FLIP L ) and a short (c-FLIP S ) splice variant. While c-FLIP S and v-FLIP are composed solely of two death effector domains, c-FLIP L contains an (inactive) caspase-like domain in addition to these two death effector domains, thereby structurally resembling proCaspase-8. Both c-FLIP L and c-FLIP S suppress apoptosis by inhibiting Caspase-8 activation, although at different levels of pro-Caspase-8 processing. To analyze the consequences of deregulated c-FLIP S expression in vivo, we established lck FLIP Stransgenic mice overexpressing the transgene in thymocytes and in mature T cells. As expected, CD95L-induced apoptosis was impaired in lck FLIP S -transgenic T cells, indicating the functionality of the FLIP S transgene. Remarkably, activation-induced cell death of transgenic T cells was unaffected, despite the observed inhibition of CD95-induced T cell death. Thymic and splenic cell numbers as well as CD4/CD8 cellularity were normal in lck FLIP S -transgenic animals, which in contrast to CD95-deficient mice do not accumulate Thy1 + B220 + CD4 -CD8 -peripheral T cells. c-FLIP S overexpression leads to a significant decrease in activation-induced T cell proliferation in vitro. Despite the capacity of FLIP S to inhibit CD95-induced apoptosis, T cell lymphomagenesis is not observed in lck FLIP S -transgenic mice. Interestingly, the Vb8 + memory T cell pool is enlarged upon staphylococcal enterotoxin B injections, suggesting a specific in vivo function for FLIP S in the maintenance of restimulated T cells. IntroductionAmong many anti-apoptotic regulatory proteins, the Caspase-8-inhibitory FLIP molecule has been studied intensively. Originally detected in different viruses, c-FLIP was eventually identified as the cellular homologue of the v-FLIP proteins ([1, 2] and references herein). Several spliced isoforms of c-FLIP have been characterized, two of which are expressed as proteins: c-FLIP L , the full-length 55-kDa form of c-FLIP, comprises two Nterminal death effector domains (DED) and an enzymatically inactive caspase domain, thereby structurally resembling . c-FLIP S is a shorter 26-kDa form of c-FLIP and, like v-FLIP, contains only the two DED.A functional pro-apoptotic death-inducing signaling complex (DISC) is usually assembled by recruitment of the adaptor protein FADD to the activated CD95 receptor via death domain interactions [3]. Due to binding of their DED, FADD then associates Caspase-8 Molecular immunologyThe first two authors contributed equally to this work. [2,5]. Recruitment of both c-FLIP L and c-FLIP S to the activated intracellular CD95 receptor complex by FADD has been demonstrated, and both proteins are able to inhibit CD95-induced apoptosis as well as cell death mediated by other death receptors [6]. It has even been suggested that c-FLIP S rather than c-FLIP L may be the prime inhibitor of CD95-mediated apoptosis in T cells [7]. Nevertheless, a recent study showed that whereas high levels of c-FLIP L o...

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Activation of the NF-κB pathway by Caspase 8 and its homologs

Cited by 222 publications

References 45 publications

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

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Activation of the NF-κB pathway by Caspase 8 and its homologs

Cited by 222 publications

References 45 publications

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort

Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

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Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection