Whole-Exome-Sequencing-Based Discovery of Human FADD Deficiency

Bolze, Alexandre; Byun, Minji; McDonald, David; Morgan, Neil V.; Abhyankar, Avinash; Premkumar, Lakshmanane; Puel, Anne; Bacon, Chris M.; Rieux-Laucat, Frédéric; Pang, Ki; Britland, Alison; Abel, Laurent; Cant, Andrew J.; Maher, Eamonn R.; Riedl, Stefan J.; Hambleton, Sophie; Casanova, Jean‐Laurent

doi:10.1016/j.ajhg.2010.10.028

Cited by 168 publications

(119 citation statements)

References 32 publications

(44 reference statements)

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“…Taken together with the earlier finding that PKR was necessary for bacterial infection-induced macrophage death (38), these observations suggest that an IFN-PKR-RIP kinase axis may control phagocyte cell fate during antibacterial immune responses. It will be interesting to see whether FADD (and/or caspases) also regulate IFN-activated macrophage necrosis during bacterial clearance, given that a hypomorphic FADD mutation in humans has been reported to increase susceptibility to bacterial infections (39).…”

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.

303

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.

303

261

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“…Yamaguchi et al 56 Glazov et al 57 Puente et al 58 Gunay-Aygun et al 59 Weedon et al 60 Homozygosity (Figure 3b Becker et al 31 Walsh et al 35 Wang et al 51a Bolze et al 61 Caliskan et al 62 Bilguvar et al 63 O'Sullivan et al 64 Barak et al 65 Hanson et al 66 Shaheen et al 67 Doi et el Only a single experiment is required.…”

Section: Affecting Protein Sequencementioning

confidence: 99%

Disease gene identification strategies for exome sequencing

et al. 2012

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“…Allergic phenotypes have been attributed more recently to certain primary immunodeficiencies (127). The genetic causes of these conditions were discovered by candidate gene approaches from 1985 onward (adenosine deaminase deficiency) (128), by positional cloning from 1986 onward (chronic granulomatous disease) (129), and by next-generation sequencing from 2010 onward (fas-associated via death domain deficiency) (130). Genetic causes have been discovered for nearly 300 single-gene inborn errors of immunity.…”

Section: Primary Immunodeficiencies: a Success Storymentioning

confidence: 99%

Human genetic basis of interindividual variability in the course of infection

Casanova

2015

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

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160

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The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue.

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Whole-Exome-Sequencing-Based Discovery of Human FADD Deficiency

Cited by 168 publications

References 32 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

Disease gene identification strategies for exome sequencing

Human genetic basis of interindividual variability in the course of infection

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