NF-κB Protects Cells from Gamma Interferon-Induced RIP1-Dependent Necroptosis

Thapa, Roshan J.; Basagoudanavar, Suresh H.; Nogusa, Shoko; Irrinki, Krishna M.; Mallilankaraman, Karthik; Slifker, Michael; Beg, Amer A.; Madesh, Muniswamy; Balachandran, Siddharth

doi:10.1128/mcb.05445-11

Cited by 119 publications

(126 citation statements)

References 67 publications

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“…Notably, HeLa cells do not express RIP3 (8) but still succumb to IFN-γ-induced RIP1-dependent necrotic death (ref. 9 and Fig. S1), indicating that IFN-γ, in a cell type-specific manner, can also activate RIP1-mediated necrosis without need for RIP3.…”

Section: Significancementioning

confidence: 93%

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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307

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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: Significancementioning

confidence: 93%

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.

Self Cite

307

261

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“…90,99 Briefly, the main events that trigger necroptosis are engagement of death receptors in the presence of caspase inhibition, 100,101 stimulation of Toll-like receptors, 92,102 signaling through interferons, 103,104 or recognition of intracellular viruses by the protein DAI. 105,106 Any of these initial triggers uses an receptor-interacting proteinhomotypic interacting motif (RHIM) domain to activate the kinase RIPK3, an essential mediator of necroptosis, [107][108][109] which itself contains an RHIM domain and phosphorylates the downstream pseudokinase 110 mixed lineage kinase domain-like (MLKL).…”

Section: Necroptosis-a Paradigm Shiftmentioning

confidence: 99%

Regulated Cell Death in AKI

Linkermann

Chen

Dong

et al. 2014

Journal of the American Society of Nephrology

466

392

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AKI is pathologically characterized by sublethal and lethal damage of renal tubules. Under these conditions, renal tubular cell death may occur by regulated necrosis (RN) or apoptosis. In the last two decades, tubular apoptosis has been shown in preclinical models and some clinical samples from patients with AKI. Mechanistically, apoptotic cell death in AKI may result from well described extrinsic and intrinsic pathways as well as ER stress. Central converging nodes of these pathways are mitochondria, which become fragmented and sensitized to membrane permeabilization in response to cellular stress, resulting in the release of cell death-inducing factors. Whereas apoptosis is known to be regulated, tubular necrosis was thought to occur by accident until recent work unveiled several RN subroutines, most prominently receptorinteracting protein kinase-dependent necroptosis and RN induced by mitochondrial permeability transition. Additionally, other cell death pathways, like pyroptosis and ferroptosis, may also be of pathophysiologic relevance in AKI. Combination therapy targeting multiple cell-death pathways may, therefore, provide maximal therapeutic benefits.

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“…In addition to the known contribution of TNF to necroptosis, type I IFN, type II IFN, and the double-stranded RNA (dsRNA) mimic poly(I:C) show the capacity to trigger this pathway in susceptible simian virus 40 (SV40)-immortalized cells (21,(30)(31)(32) …”

Section: Casp8mentioning

confidence: 99%

RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition

Kaiser

Daley‐Bauer

Thapa

et al. 2014

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

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263

287

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Significance The protein kinase receptor interacting protein 1 controls signaling via death receptors, Toll-like receptors, and retinoic acid-inducible gene 1-like receptors, dictating inflammatory outcomes as broad as cytokine activation and cell death. RIP1 makes a vital contribution during development, evident from the fact that RIP1-deficient mice die soon after birth. Here, we show that a kinase-independent function of RIP1 dampens the consequences of innate immune cell death. During parturition, RIP1 prevents the lethal consequences of RIP3-dependent necroptosis as well as caspase 8 (Casp8)-dependent apoptosis. In contrast to the RIP1-deficient phenotype, mice lacking a combination of RIP1, RIP3, and Casp8 are born and mature into viable, fertile, and immunocompetent adults. These results demonstrate the important protective role of RIP1 against physiologic and microbial death cues encountered at birth.

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NF-κB Protects Cells from Gamma Interferon-Induced RIP1-Dependent Necroptosis

Cited by 119 publications

References 67 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

Regulated Cell Death in AKI

RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition

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