Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity

Lu, Jennifer; Weist, Brian M.; Raam, Bram J. van; Marro, Brett S.; Nguyen, Long V.; Srinivas, Prathna; Bell, Bryan D.; Luhrs, Keith A.; Lane, Thomas E.; Salvesen, Guy S.; Walsh, Craig M.

doi:10.1073/pnas.1102779108

Cited by 112 publications

(118 citation statements)

References 39 publications

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“…In the context of a virus infection, activating PKR (either directly by virus RNA or indirectly via production of type I IFNs) can initiate necrosis in G 2 /M when FADD is phosphorylated and consequent PKR necrosome formation is licensed. In a similar manner, cells in which FADD/caspase expression or function have been compromised by virus infection [for example, by virally encoded inhibitors of apoptosis (31) Recent studies have shown that FADD-in addition to regulating IFN-activated necrosis as reported in this study-also controls the activity of RIP1/3 kinases to (i) restrict fulminant inflammatory tissue damage in the gut and skin, (ii) prevent inopportune T-cell necrosis during development and immune responses, and (iii) allow normal progression through embryogenesis (16,(32)(33)(34)(35)(36). In each of these scenarios, the upstream signals that activate RIP1/3 when FADD is absent remain vague (4).…”

Section: Discussionmentioning

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.

302

261

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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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Section: Discussionmentioning

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.

302

261

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“…Activity of RIPK1 and RIPK3, that modulate necrosis and autophagy, is limited by their cleavage by caspase-8, which results in limitation of autophagy and necrosis. Only in the absence of robust caspase-8 activity a stable complex between RIPK1 and RIPK3 is formed, promoting programmed necrosis and autophagy (instead of apoptosis) (Lu et al 2011). Death receptor signaling via RIPK1 and RIPK3 has also been studied in a model involving the assembly of DISC in isolated membranes/pre-autophagosomal structures (PAS).…”

Section: Other Interconnections Between Apoptotic Necrotic and Autopmentioning

confidence: 99%

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Chaabane

User

El-Gazzah

et al. 2012

Arch. Immunol. Ther. Exp.

251

149

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“…Although FADD is found in the necrosome complex and is regarded as an adaptor protein that links DRs to the RIP1-RIP3 complex 9,31,32,42 , it appears to function as a negative regulator of necroptosis under various conditions 5,7,10,11,43 . To determine the exact function of FADD in necrosome formation in relation to MKRN1, we first depleted FADD in L929 and HT-29 cells.…”

Section: Fadd Stabilization Upon Mkrn1 Depletion Prevents Necroptosismentioning

confidence: 99%

Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

et al. 2012

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Fas-associated protein with death domain (FADD) is a pivotal component of death receptormediated extrinsic apoptosis and necroptosis. Here we show that FADD is regulated by makorin Ring Finger Protein 1 (mKRn1) E3 ligase-mediated ubiquitination and proteasomal degradation. mKRn1 knockdown results in FADD protein stabilization and formation of the rapid deathinducing signalling complex, which causes hypersensitivity to extrinsic apoptosis by facilitating caspase-8 and caspase-3 cleavage in response to death signals. We also show that mKRn1 and FADD are involved in the regulation of necrosome formation and necroptosis upon caspase inhibition. Downregulation of mKRn1 results in severe defects of tumour growth upon tumour necrosis factor-related apoptosis-inducing ligand treatment in a xenograft model using mDAmB-231 breast cancer cells. suppression of tumour growth by mKRn1 depletion is relieved by simultaneous FADD knockdown. our data reveal a novel mechanism by which fas-associated protein with death domain is regulated via an ubiquitination-induced degradation pathway. A poptosis, or programmed cell death, can be initiated by intrinsic or extrinsic pathways 1,2 . Intrinsic pathways are triggered by mitochondrial permeabilization, which results in the release of cytochrome c and the formation of an apoptosome complex, leading to caspase-9 activation 3 . Extrinsic pathways can be induced by activation of death receptors (DRs), such as TNFR1, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and Fas/CD95 by their corresponding ligands; receptor activation triggers the formation of the death-inducing signalling complex (DISC) or TNFR complex II, which comprises caspase-8 and fas-associated protein with death domain (FADD). These complexes ultimately activate caspase-8, thereby causing extrinsic apoptosis 3,4 . In addition to inducing extrinsic apoptosis, caspase-8 and FADD are known to suppress necroptosis under various conditions [5][6][7][8][9][10][11] .DR downstream pathways are regulated in various ways. For example, cFLIP (cellular FLICE inhibitory protein) competes with caspase-8 for binding to FADD, preventing DISC formation 12 . The levels and activities of cFLIP are controlled by numerous factors including NF-κB, Akt, JNK, Srk and ITCH [13][14][15][16][17] . CARP-1 and -2, which are E3 ubiquitin ligases for caspase-8, are also known to suppress TRAIL activation 18 . Post-translational modifications such as O-glycosylation, S-nitrosylation and S-palmitoylation of DRs have also been identified to regulate death signalling 19 . However, phosphorylation of FADD, the only post-translational modification that FADD is known to undergo, is not involved in the induction of apoptosis. Rather, this modification seems to be essential for the pro-survival roles of nuclear-localized phospho-FADD [20][21][22][23] . Other post-translational modifications affecting the apoptotic and necroptotic activities of FADD have yet to be identified.Here, we show that Makorin Ring Finger Protein 1 (MKRN1), an...

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Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity

Cited by 112 publications

References 39 publications

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

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

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis

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