Requirement of FADD, NEMO, and BAX/BAK for Aberrant Mitochondrial Function in Tumor Necrosis Factor Alpha-Induced Necrosis

Irrinki, Krishna M.; Mallilankaraman, Karthik; Thapa, Roshan J.; Chandramoorthy, Harish C.; Smith, Frederick M.; Jog, Neelakshi R.; Gandhirajan, Rajesh Kumar; Kelsen, Steven G.; Houser, Steven R.; May, Michael J.; Balachandran, Siddharth; Madesh, Muniswamy

doi:10.1128/mcb.05303-11

Cited by 98 publications

(91 citation statements)

References 72 publications

(91 reference statements)

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“…Indeed, FADD was detected in TNF-induced complex II and necrosome complex in numerous studies (Fig. 2B) (22,78,79,118,119). Since FADD is required for full activation of caspase-8, both FADD and caspase-8 are required for apoptosis (Fig.…”

Section: The Roles Of Fadd On Apoptosis and Necroptosis In Vitro And mentioning

confidence: 95%

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The roles of FADD in extrinsic apoptosis and necroptosis

et al. 2012

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Fas-associated protein with death domain (FADD), an adaptor that bridges death receptor signaling to the caspase cascade, is indispensible for the induction of extrinsic apoptotic cell death. Interest in the non-apoptotic function of FADD has greatly increased due to evidence that FADD-deficient mice or dominant-negative FADD transgenic mice result in embryonic lethality and an immune defect without showing apoptotic features. Numerous studies have suggested that FADD regulates cell cycle progression, proliferation, and autophagy, affecting these phenomena. Recently, programmed necrosis, also called necroptosis, was shown to be a key mechanism that induces embryonic lethality and an immune defect. Supporting these findings, FADD was shown to be involved in various necroptosis models. In this review, we summarize the mechanism of extrinsic apoptosis and necroptosis, and discuss the in vivo and in vitro roles of FADD in necroptosis induced by various stimuli.[BMB Reports 2012; 45(9): 496-508] INTRODUCTIONFas-associated protein with death domain (FADD) is a critical adaptor protein for death receptor (DR)-mediated apoptosis. FADD is composed of two domains called the death domain (DD) and death effector domain (DED). The DD of FADD binds to the DD of the death receptor and FADD recruits procaspase-8 through the DED-DED interaction, forming a death-inducing signaling complex (DISC), where procaspase-8 is activated by self-cleavage. Active caspase-8 cleaves downstream effector caspases such as caspase-3, -6, and -7, inducing apoptosis. Interestingly, FADD deficiency results in embryonic lethality, displaying a defect in immune homeostasis and immune cell proliferation despite the defect in inducing apoptosis. In addition, FADD is also implicated in non-apoptotic functions such as cell cycle progression, proliferation, autophagy, inflammation and innate immunity (1, 2). Particularly, FADD phosphorylation at Ser194 (pFADD) by several kinases is associated with its nuclear localization and cell cycle regulation (3-8). Although FADD and pFADD are often overexpressed in various tumors, their functions in cancer development or chemotherapy-sensitivity are still controversial (9-14). Recent strong evidence from in vivo mice studies suggested negative roles of FADD in RIP1-and RIP3-dependent necroptosis (15-18). DR-mediated caspase-8 activation requires FADD, and leads to the cleavage of RIP1, RIP3, and CYLD, preventing necroptosis (19)(20)(21)(22). Thus, FADD deficiency is thought to inhibit caspase-8 and subsequent apoptosis, but activate necroptosis. Since necroptosis can be initiated by various stimuli in a variety of cell types independently of DRs, the exact mechanisms and functions of FADD require further investigation. This review focuses on the recent discoveries about the roles of FADD in apoptosis and necroptosis in various models, and we refer the reader to two comprehensive reviews of the diverse functions of FADD (1, 2). EXTRINSIC APOPTOSIS Molecular mechanism of extrinsic apoptosisExtrinsic apoptosis, which is...

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Section: The Roles Of Fadd On Apoptosis and Necroptosis In Vitro And mentioning

confidence: 95%

“…2E). FADD KO MEF exhibited resistance to TNF-induced necroptosis (118). On the other hand, many reports have suggested negative roles of FADD in TNF-induced necroptosis.…”

Section: The Roles Of Fadd On Apoptosis and Necroptosis In Vitro And mentioning

confidence: 95%

The roles of FADD in extrinsic apoptosis and necroptosis

et al. 2012

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“…TCZ, TNF-α (50 ng/mL) plus cycloheximide (500 ng/mL) plus z-VAD (50 μM). Note that TCZ-induced necrosome formation was examined in fadd +/+ MEFs, as TNF-α, unlike IFN-γ, requires FADD to assemble the necrosome in MEFs (30). (E and F) Nec-1 (50 μM) pretreatment does not prevent IFN-γ (5 ng/mL)-driven necrosome formation (E) but efficiently prevents TNF-α-induced necrosome formation in fadd +/+ MEFs (F).…”

Section: Significancementioning

confidence: 99%

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

Thapa

Nogusa

Chen

et al. 2013

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

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Interferons (IFNs) are cytokines with powerful immunomodulatory and antiviral properties, but less is known about how they induce cell death. Here, we show that both type I (α/β) and type II (γ) IFNs induce precipitous receptor-interacting protein (RIP)1/RIP3 kinasemediated necrosis when the adaptor protein Fas-associated death domain (FADD) is lost or disabled by phosphorylation, or when caspases (e.g., caspase 8) are inactivated. IFN-induced necrosis proceeds via progressive assembly of a RIP1-RIP3 "necrosome" complex that requires Jak1/STAT1-dependent transcription, but does not need the kinase activity of RIP1. Instead, IFNs transcriptionally activate the RNA-responsive protein kinase PKR, which then interacts with RIP1 to initiate necrosome formation and trigger necrosis. Although IFNs are powerful activators of necrosis when FADD is absent, these cytokines are likely not the dominant inducers of RIP kinase-driven embryonic lethality in FADD-deficient mice. We also identify phosphorylation on serine 191 as a mechanism that disables FADD and collaborates with caspase inactivation to allow IFN-activated necrosis. Collectively, these findings outline a mechanism of IFN-induced RIP kinase-dependent necrotic cell death and identify FADD and caspases as negative regulators of this process.necroptosis | apoptosis I nterferons (IFNs) are pleiotropic cytokines classified into two primary groups, type I (predominantly α/β) and type II (γ). Both classes of IFNs exert their effects via similar Janus kinase (JAK)-signal transducers and activators of transcription (STAT)-dependent signaling cascades to induce the expression of over 500 genes (1). Such IFN-stimulated genes (ISGs) have been reasonably well characterized in the context of antiviral or immune-modulatory signaling, but less is known about how they collaborate to mediate the cytotoxic and antiproliferative effects of IFNs.Recent studies have shed light on a new form of regulated cell death that is activated when caspase-dependent apoptotic pathways are inhibited. This mode of necrotic cell death, sometimes called "necroptosis," requires the serine-threonine kinases receptor-interacting protein 1 (RIP1) and RIP3, and results from overproduction of reactive oxygen species (ROS) and eventual mitochondrial dysfunction (2, 3). Strict negative control of the pronecrotic kinases RIP1 and RIP3 are essential for several aspects of mammalian development and homeostasis, including immune cell proliferation and progression through embryogenesis (4). The proteins FADD, caspase 8, and c-FLIP represent three such negative regulators; in the absence of any of these molecules, the RIP kinases trigger inopportune necrosis, often with severe consequences for the host (4). The core necrosis machinery is thus carefully regulated to execute cell death only in specific contexts, but how this regulation is achieved and which other upstream stimuli exploit RIP kinases to activate necrosis are still relatively poorly described.In the present study, we show that both IFN-γ and IFN-α/β t...

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“…Activation of tumor necrosis factor (TNF) receptors under conditions of caspase-8 inhibition leads to the formation of the necrosome, a complex consisting of the serine/threonine kinases receptor interacting proteins (RIP, or RIPK) 1 and 3 (Cho et al, 2009;He et al, 2009;Zhang et al, 2009;Li et al, 2012). This complex in turn has been proposed to facilitate necrotic killing through a variety of mechanisms, including activation of NADPH oxidases (Kim et al, 2007), induction of mitochondrial reactive oxygen species (Irrinki et al, 2011;Vanlangenakker et al, 2011) and activation of the pseudokinase mixed lineage kinase like (MLKL) with subsequent activation of the mitochondrial-associated phosphatase PGAM5 (Sun et al, 2012;Wang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways

Douglas

Baines

2014

Journal of Cell Science

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Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme that can trigger caspase-independent necrosis. Two main mechanisms for this have been proposed: one involving RIP1 and JNK kinases and mitochondrial permeability transition (MPT), the other involving calpain-mediated activation of Bax and mitochondrial release of apoptosis-inducing factor (AIF). However, whether these two mechanisms represent distinct pathways for PARP1-induced necrosis, or whether they are simply different components of the same pathway has yet to be tested. Mouse embryonic fibroblasts (MEFs) were treated with either N-methyl-N9-nitro-N-nitrosoguanidine (MNNG) or b-Lapachone, resulting in PARP1-dependent necrosis. This was associated with increases in calpain activity, JNK activation and AIF translocation. JNK inhibition significantly reduced MNNGand b-Lapachone-induced JNK activation, AIF translocation, and necrosis, but not calpain activation. In contrast, inhibition of calpain either by Ca 2+ chelation or knockdown attenuated necrosis, but did not affect JNK activation or AIF translocation. To our surprise, genetic and/or pharmacological inhibition of RIP1, AIF, Bax and the MPT pore failed to abrogate MNNG-and b-Lapachone-induced necrosis. In conclusion, although JNK and calpain both contribute to PARP1-induced necrosis, they do so via parallel mechanisms.

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Requirement of FADD, NEMO, and BAX/BAK for Aberrant Mitochondrial Function in Tumor Necrosis Factor Alpha-Induced Necrosis

Cited by 98 publications

References 72 publications

The roles of FADD in extrinsic apoptosis and necroptosis

The roles of FADD in extrinsic apoptosis and necroptosis

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways

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