The c-FLIPL Cleavage Product p43FLIP Promotes Activation of Extracellular Signal-regulated Kinase (ERK), Nuclear Factor κB (NF-κB), and Caspase-8 and T Cell Survival

Koenig, Andreas; Buskiewicz, Iwona; Fortner, Karen A.; Russell, Jennifer Q.; Asaoka, Tomoko; He, You–Wen; Hakem, Razqallah; Eriksson, John E.; Budd, Ralph C.

doi:10.1074/jbc.m113.506428

Cited by 39 publications

(43 citation statements)

References 40 publications

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“…In addition to controlling cell-extrinsic death, caspase-8 also plays a role in NF-κB signaling and gene expression (31,32,38,39), potentially via cleavage of cFLIP (40,41). However, YopJinduced caspase-1 activation and cell death via caspase-8 and FADD are independent of LPS-induced priming, because they are triggered by NF-κB inhibition and are independent of ASC, NLRP3, and IFNAR.…”

Section: Discussionmentioning

confidence: 99%

Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

Philip

Dillon²,

Snyder

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

236

253

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Toll-like receptor signaling and subsequent activation of NF-κB-and MAPK-dependent genes during infection play an important role in antimicrobial host defense. The YopJ protein of pathogenic Yersinia species inhibits NF-κB and MAPK signaling, resulting in blockade of NF-κB-dependent cytokine production and target cell death. Nevertheless, Yersinia infection induces inflammatory responses in vivo. Moreover, increasing the extent of YopJ-dependent cytotoxicity induced by Yersinia pestis and Yersinia pseudotuberculosis paradoxically leads to decreased virulence in vivo, suggesting that cell death promotes anti-Yersinia host defense. However, the specific pathways responsible for YopJ-induced cell death and how this cell death mediates immune defense against Yersinia remain poorly defined. YopJ activity induces processing of multiple caspases, including caspase-1, independently of inflammasome components or the adaptor protein ASC. Unexpectedly, caspase-1 activation in response to the activity of YopJ required caspase-8, receptor-interacting serine/threonine kinase 1 (RIPK1), and Fas-associated death domain (FADD), but not RIPK3. Furthermore, whereas RIPK3 deficiency did not affect YopJ-induced cell death or caspase-1 activation, deficiency of both RIPK3 and caspase-8 or FADD completely abrogated Yersinia-induced cell death and caspase-1 activation. Mice lacking RIPK3 and caspase-8 in their hematopoietic compartment showed extreme susceptibility to Yersinia and were deficient in monocyte and neutrophil-derived production of proinflammatory cytokines. Our data demonstrate for the first time to our knowledge that RIPK1, FADD, and caspase-8 are required for YopJ-induced cell death and caspase-1 activation and suggest that caspase-8-mediated cell death overrides blockade of immune signaling by YopJ to promote anti-Yersinia immune defense.innate immunity | apoptosis | programmed necrosis | macrophage | pyroptosis

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Section: Discussionmentioning

confidence: 99%

Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

Philip

Dillon²,

Snyder

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

236

253

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“…cFLIP L was initially shown to have an inhibitory role in CD95-induced NF-κB activation (34, 121), but it was later demonstrated that it is the c-terminal domain of cFLIP L that inhibits the interaction between the DD of RIPK1 and the prodomain of caspase-8 that is required for CD95-induced NF-κB activation (122). Processing of full-length cFLIP L to p43/p22 by caspase-8 in the FADD-caspase-8-cFLIP L complex mediates NF-κB activation (123) by allowing cFLIP L p43 to interact with TRAF2 (124), RIPK1 and the IKK complex. Furthermore, the p22 fragment of processed cFLIP L was shown to be able to induce NF-κB activation by interacting with NEMO in the IKK complex (125).…”

Section: Non-cell Death Roles Of Caspase-8mentioning

confidence: 99%

Caspase‐8: regulating life and death

Tummers

Green

2017

Immunological Reviews

577

421

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Summary Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Whereas excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediatedactivation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.

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“…In addition to its involvement in apoptosis modulation, c-FLIP plays important roles in controlling proliferation [26] and cardiac hypertrophy after pressure overload [27]. Furthermore, c-FLIP can activate several pro-survival signalling pathways by regulating proteins such as NF-κB, ERK and AKT [28][29][30]. More recently, we demonstrated that c-FLIP −/− mouse embryonic fibroblasts (MEFs) display an enlarged ER structure and strong lipid accumulation [22,31].…”

Section: Introductionmentioning

confidence: 97%

A novel role of c-FLIP protein in regulation of ER stress response

Conti

Petrungaro

Marini

et al. 2016

Cellular Signalling

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Cellular-Flice-like inhibitory protein (c-FLIP) is an apoptosis modulator known to inhibit the extrinsic apoptotic pathway thus blocking Caspase-8 processing in the Death Inducing Signalling Complex (DISC). We previously demonstrated that c-FLIP localizes at the endoplasmic reticulum (ER) and that c-FLIP-deficient mouse embryonic fibroblasts (MEFs) display an enlarged ER morphology. In the present study, we have addressed the consequences of c-FLIP ablation in the ER stress response by investigating the effects of pharmacologically-induced ER stress in Wild Type (WT) and c-FLIP-/- MEFs. Surprisingly, c-FLIP-/- MEFs were found to be strikingly more resistant than WT MEFs to ER stress-mediated apoptosis. Analysis of Unfolded Protein Response (UPR) pathways revealed that Pancreatic ER Kinase (PERK) and Inositol-Requiring Enzyme 1 (IRE1) branch signalling is compromised in c-FLIP-/- cells when compared with WT cells. We found that c-FLIP modulates the PERK pathway by interfering with the activity of the serine threonine kinase AKT. Indeed, c-FLIP-/- MEFs display higher levels of active AKT than WT MEFs upon ER stress, while treatment with a specific AKT inhibitor of c-FLIP-/- MEFs subjected to ER stress restores the PERK but not the IRE1 pathway. Importantly, the AKT inhibitor or dominant negative AKT transfection sensitizes c-FLIP-/- cells to ER stress-induced cell death while the expression of a constitutively active AKT reduces WT cells sensitivity to ER stress-induced death. Thus, our results demonstrate that c-FLIP modulation of AKT activity is crucial in controlling PERK signalling and sensitivity to ER stress, and highlight c-FLIP as a novel molecular player in PERK and IRE1-mediated ER stress response.

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The c-FLIPL Cleavage Product p43FLIP Promotes Activation of Extracellular Signal-regulated Kinase (ERK), Nuclear Factor κB (NF-κB), and Caspase-8 and T Cell Survival

Cited by 39 publications

References 40 publications

Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

Caspase‐8: regulating life and death

A novel role of c-FLIP protein in regulation of ER stress response

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