Modulation of Wnt signaling by the nuclear localization of cellular FLIP-L

Katayama, Ryohei; Ishioka, Toshiyasu; Takada, Shinji; Takada, Ritsuko; Fujita, Naoya; Tsuruo, Takashi; Naito, Mikihiko

doi:10.1242/jcs.058602

Cited by 26 publications

(32 citation statements)

References 36 publications

(32 reference statements)

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“…While this region shares some homology to the procaspase-8 caspase domain, the cFLIP L caspase-like domain (CLD) lacks caspase activity because there are several amino acid substitutions in the region required for caspase activity (41). The C-terminal region also possesses nuclear localization sequences (NLS) at residues 435–437 and 472–474 (44). …”

Section: Resultsmentioning

confidence: 99%

“…cFLIP L is often regarded as a cytoplasmic protein because it interacts with other cytoplasmic proteins including procaspase-8 (34). However, the cFLIP L C-terminus possesses two NLS’s and it has been shown that cFLIP L is present in the nucleus (44). Thus, it was not surprising to detect wild-type cFLIP L or mutant CLD protein in the nucleus and cytoplasm (Fig.…”

Section: Resultsmentioning

confidence: 99%

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cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

Gates

Shisler

2016

The Journal of Immunology

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Type I interferon (IFN) induction is critical for anti-viral and anti-cancer defenses. Proper down-regulation of type I IFN is equally important to avoid deleterious imbalances in the immune response. The cellular FLIP long isoform protein (cFLIPL) controls type I IFN production, but opposing publications show it as either an inhibitor or inducer of type I IFN synthesis. Regardless, the mechanistic basis for cFLIPL regulation is unknown. Because cFLIPL is important in immune cell development and proliferation, and is a target for cancer therapies, it is important to identify how cFLIPL regulates type I IFN production. Data here show that cFLIPL inhibits IRF3, a transcription factor central for IFNβ and ISG expression. This inhibition occurs during virus infection, cellular exposure to poly I:C or TBK1 over-expression. This inhibition is independent of capase-8 activity. cFLIPL binds to IRF3 and disrupts IRF3 interaction with its IFNβ promoter and its co-activator protein (CBP). Mutational analyses reveal that cFLIPL nuclear localization is necessary and sufficient for inhibitory function. This suggests that nuclear cFLIPL prevents IRF3 enhanceosome formation. Unlike other cellular IRF3 inhibitors, cFLIPL did not degrade or dephosphorylate IRF3. Thus, cFLIPL represents a different cellular strategy to inhibit type I IFN production. This new cFLIPL function must be considered to accurately understand how cFLIPL affects immune system development and regulation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

Gates

Shisler

2016

The Journal of Immunology

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“…Clearly, the balance between cFLIP and caspase-8 is of greater importance for the latter in inducing apoptosis than for the former. Further studies underlining the role and mechanism of cFLIP levels and translocation to the cytoplasm by the nuclear export and import signals on cFLIP (30,31) are required to shed light on the nature of this mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…The cFLIP gene encodes two isoforms, long and short (29). The cFLIP long isoform (cFLIP L ) contains both nuclear localization and export signals in the caspase-like domain, promoting its translocation into and out of the nucleus (28,30,31). Nuclear translocation of cFLIP was previously described to modulate Wnt signaling, but the apoptotic effect was not addressed.…”

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confidence: 99%

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

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Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-␥) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

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“…By contrast, c-FLIP L contains a longer C-terminal caspase-like domain, which is not active [18,19]. The structural differences between the c-FLIP isoforms correlate with a different cellular localization and function; indeed, c-FLIP S,R are found in the cytosol alone, whereas c-FLIP L localizes in the nucleus, cytoplasm, ER and Mitochondria-Associated Membranes (MAMs) [20][21][22]. Moreover, whereas the anti-apoptotic role of c-FLIP S,R has been widely demonstrated, c-FLIP L has been reported to exert the opposite effect on apoptosis regulation; c-FLIP L has been shown to block Fas-induced Caspase-8 activation when expressed at high levels, but to act as a pro-apoptotic molecule when its expression level is moderate [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

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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Modulation of Wnt signaling by the nuclear localization of cellular FLIP-L

Cited by 26 publications

References 36 publications

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

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

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