The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation

Park, Hyun Ho; Lo, Yu‐Chieh; Lin, Su Chang; Wang, Liwei; Yang, Jin Kuk; Wu, Hao

doi:10.1146/annurev.immunol.25.022106.141656

Cited by 456 publications

(456 citation statements)

References 143 publications

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“…Concerning the acute modulation of FADD by cocaine, and in regard to its regulation of apoptotic vs nonapoptotic events, we examined the impact of cocaine exposure on the phosphorylated form of FADD, recently described as a nonapoptotic marker (Alappat et al, 2005;Park et al, 2005Park et al, , 2007Chen et al, 2005;Bhojani et al, 2005), and PARP, an enzyme cleaved by the protease caspase-3, as an apoptotic marker (Cagnol et al, 2006). Acute cocaine treatment induced significant decreases in pFADD protein content, and as judged from levels of PARP protein activation, did not appear to induce apoptosis in the brain cortex, at least Note that NF-L was immunodetected in F4 but not in the other subcellular fractions.…”

Section: Effects Of Cocaine On Fadd In the Rat Brain Cortexmentioning

confidence: 99%

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

García-Fuster

Clinton

Watson

et al. 2008

Neuropsychopharmacol

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This study was designed to (1) assess the effects of cocaine on Fas-associated protein with death domain (FADD) system and its role in the activation of apoptotic vs nonapoptotic events and (2) ascertain whether animals selectively bred for their differential propensity to drug-seeking show differences in FADD levels or response to cocaine. Acute cocaine, through D 2 dopamine receptors, induced a doseresponse increase in FADD protein in the cortex, with opposite effects over pFADD (Ser191/194), and no induction of apoptotic cell death (poly-(ADP-ribose) polymerase cleavage). FADD was increased by cocaine in cytosol (B142%), membranes (B23%) and nucleus (B54%). The modulation of the FADD system showed tolerance of the acute effect over time, as well as a compensatory response on withdrawal that mirrored the acute effectFie a transient FADD decrease on day 3 of withdrawal, both at mRNA and protein levels. In a second experiment, possible FADD differences were investigated in rats selectively bred for differential responsiveness to novelty, propensity for drug-seeking and cocaine sensitization. High-responders (HR), who were more prone to drug abuse, exhibited higher FADD and lower pFADD levels than low-responder (LR) rats. However, HR and LR rats showed similar rates of cocaine-induced apoptosis, and exhibited a parallel impact of cocaine over FADD within each phenotype. Thus, FADD is a signaling protein modulated by cocaine, regulating apoptosis/proliferative mechanisms in relation to its FADD/pFADD content. Interestingly, animals selectively bred for differential propensity to substance abuse show basal differences in the expression of this protein, suggesting FADD may also be a molecular correlate for the HR/LR phenotype.

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Section: Effects Of Cocaine On Fadd In the Rat Brain Cortexmentioning

confidence: 99%

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

García-Fuster

Clinton

Watson

et al. 2008

Neuropsychopharmacol

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“…Apoptosis, a well‐studied programmed cell death, is critical for tissue development and homeostasis 14. Therefore, the fluctuation of apoptosis level under different conditions may lead to serious diseases or outcome of them 15.…”

Section: Introductionmentioning

confidence: 99%

Reoxygenation Reverses Hypoxic Pulmonary Arterial Remodeling by Inducing Smooth Muscle Cell Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial Dysfunction

Chen

Wang

Dong

et al. 2017

JAHA

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BackgroundPulmonary arterial remodeling, a main characteristic of hypoxic pulmonary hypertension, can gradually reverse once oxygen has been restored. Previous studies documented that apoptosis increased markedly during the reversal of remodeled pulmonary arteries, but the types of cells and mechanisms related to the apoptosis have remained elusive. This study aimed to determine whether pulmonary artery smooth muscle cell (PASMC)‐specific apoptosis was involved in the reoxygenation‐induced reversal of hypoxic pulmonary arterial remodeling and elucidate the underlying mechanism.Methods and ResultsHypoxic pulmonary hypertension was induced in adult male Sprague‐Dawley rats (n=6/group) by chronic hypobaric hypoxia. and the hypoxic pulmonary hypertension rats were then transferred to a normoxia condition. During reoxygenation, hypoxia‐induced pulmonary arterial remodeling gradually reversed. The reversal of remodeled pulmonary arteries was associated with increased H2O2 and with changes in lung expression of cleaved caspase3/PARP, Bax, and Bcl‐2, consistent with increased apoptosis. The PASMC apoptosis, in particular, increased remarkably during this reversal. In vitro, reoxygenation induced the apoptosis of cultured rat primary PASMCs accompanied by increased mitochondrial reactive oxygen species, mitochondrial dysfunction, and the release of cytochrome C from mitochondria to cytoplasm. Clearance of reactive oxygen species alleviated mitochondrial dysfunction as well as the release of cytochrome C and, finally, decreased PASMC apoptosis.ConclusionsReoxygenation‐induced apoptosis of PASMCs is implicated in the reversal of hypoxic pulmonary arterial remodeling, which may be attributed to the mitochondrial reactive oxygen species–mediated mitochondrial dysfunction.

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“…10,11 The DED forms a bundle of six antiparallel a-helices similar to the death domain (DD) and the caspase recruitment domain (CARD), two other signaling motifs involved in homotypic protein interactions. 12 Curiously, despite their importance in apoptosis, there are currently no reported structures for cellular FLIP proteins. Only the structure of the tandem DEDs of the v-FLIP MC159 from Molluscum contagiosum has been reported showing a rigidly associated dumbbell-shaped molecule, which is tightly packed by an extensive hydrophobic interface between its two DEDs.…”

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confidence: 99%

Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment

et al. 2008

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Cellular FLICE-inhibitory protein (c-FLIP) proteins are known as potent inhibitors of death receptor-mediated apoptosis by interfering with caspase-8 activation at the death-inducing signaling complex (DISC). Among the three human isoforms, c-FLIP long , c-FLIP short and c-FLIP R , the latter isoform is poorly characterized. We report here the characterization of murine c-FLIP R and show that it is the only short c-FLIP isoform expressed in mice. By generating several mutants, we demonstrate that both death effector domains (DEDs) are required for DISC binding and the antiapoptotic function of c-FLIP R . Surprisingly, the C-terminal tail is important for both protein stability and DISC recruitment. Three-dimensional modeling of c-FLIP R revealed a substantial similarity of the overall structures and potential interaction motifs with the viral FLIP MC159. We found, however, that c-FLIP R uses different structural motifs for its DISC recruitment. Whereas MC159 interferes with interaction and selfoligomerization of the DISC component FADD by its extensive hydrophilic surface, a narrow hydrophobic patch of c-FLIP R on the surface of DED2 is crucial for DISC association. Thus, despite the presence of similar tandem DEDs, viral and cellular FLIPs inhibit apoptosis by remarkably divergent mechanisms. Death receptors like CD95 (Fas/Apo-1) transduce death signals upon ligand binding and formation of a death-inducing signaling complex (DISC), which comprises the receptor, the adaptor protein Fas-associated death domain (FADD) and procaspase-8 (FLICE) or procaspase-10. 1 This assembly brings procaspase-8/10 in close proximity to the receptor and allows them to be activated by dimerization. 2-4 Activation of the initiator caspases can be counteracted by FLICEinhibitory proteins (FLIPs). 5,6 Next to viral FLIP (v-FLIP) proteins, 7 three cellular homologs (cellular FLICE-inhibitory proteins (c-FLIPs)) have been identified, namely c-FLIP long , c-FLIP short and c-FLIP R , which are generated by differential splicing. [8][9][10] The C-terminus of c-FLIP long contains a catalytically inactive caspase-like domain, whereas c-FLIP short and c-FLIP R have only a truncated C-terminus.As a characteristic feature, FLIP proteins contain tandem death effector domains (DEDs), which mediate their recruitment into the DISC. 10,11 The DED forms a bundle of six antiparallel a-helices similar to the death domain (DD) and the caspase recruitment domain (CARD), two other signaling motifs involved in homotypic protein interactions. 12 Curiously, despite their importance in apoptosis, there are currently no reported structures for cellular FLIP proteins. Only the structure of the tandem DEDs of the v-FLIP MC159 from Molluscum contagiosum has been reported showing a rigidly associated dumbbell-shaped molecule, which is tightly packed by an extensive hydrophobic interface between its two DEDs. 13,14 Similar to FADD, each DED of MC159 contains two prominent surface features important for protein interactions that distinguish them from other death mot...

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The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation

Cited by 456 publications

References 143 publications

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

Effect of Cocaine on Fas-Associated Protein with Death Domain in the Rat Brain: Individual Differences in a Model of Differential Vulnerability to Drug Abuse

Reoxygenation Reverses Hypoxic Pulmonary Arterial Remodeling by Inducing Smooth Muscle Cell Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial Dysfunction

Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment

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