scholarly journals Full-length Fas-associated Death Domain Protein Interacts with Short Form of Cellular FLICE Inhibitory Protein

2006 ◽  
Vol 27 (1) ◽  
pp. 87-92 ◽  
Keyword(s):  
Short Form ◽  
Full Length ◽  
Death Domain ◽  
Inhibitory Protein ◽  
Domain Protein

scholarly journals Hepatitis C Virus Core Protein Inhibits Tumor Necrosis Factor Alpha-Mediated Apoptosis by a Protective Effect Involving Cellular FLICE Inhibitory Protein

2006 ◽  
Vol 80 (9) ◽  
pp. 4372-4379 ◽  
Author(s):  
Kousuke Saito ◽  
Keith Meyer ◽  
Rebecca Warner ◽  
Arnab Basu ◽  
Ratna B. Ray ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Core Protein ◽  
Death Domain ◽  
Inhibitory Protein ◽  
Necrosis Factor Alpha ◽  
Hcv Core Protein ◽  
Tnf Α ◽  
Factor Alpha ◽  
Domain Protein ◽  
Necrosis Factor

ABSTRACT We have previously shown that hepatitis C virus (HCV) core protein modulates multiple cellular processes, including those that inhibit tumor necrosis factor alpha (TNF-α)-mediated apoptosis. In this study, we have investigated the signaling mechanism for inhibition of TNF-α-mediated apoptosis in human hepatoma (HepG2) cells expressing core protein alone or in context with other HCV proteins. Activation of caspase-3 and the cleavage of DNA repair enzyme poly(ADP-ribose) polymerase were inhibited upon TNF-α exposure in HCV core protein-expressing HepG2 cells. In vivo protein-protein interaction studies displayed an association between TNF receptor 1 (TNFR1) and TNFR1-associated death domain protein (TRADD), suggesting that the core protein does not perturb this interaction. A coimmunoprecipitation assay also suggested that HCV core protein does not interfere with the TRADD-Fas-associated death domain protein (FADD)-procaspase-8 interaction. Further studies indicated that HCV core protein expression inhibits caspase-8 activation by sustaining the expression of cellular FLICE (FADD-like interleukin-1β-converting enzyme)-like inhibitory protein (c-FLIP). Similar observations were also noted upon expression of core protein in context to other HCV proteins expressed from HCV full-length plasmid DNA or a replicon. A decrease in endogenous c-FLIP by specific small interfering RNA induced TNF-α-mediated apoptotic cell death and caspase-8 activation. Taken together, our results suggested that the TNF-α-induced apoptotic pathway is inhibited by a sustained c-FLIP expression associated with the expression of HCV core protein, which may play a role in HCV-mediated pathogenesis.

scholarly journals Activation of caspases-8 and -10 by FLIPL

2004 ◽  
Vol 382 (2) ◽  
pp. 651-657 ◽  
Author(s):  
Kelly M. BOATRIGHT ◽  
Cristina DEIS ◽  
Jean-Bernard DENAULT ◽  
Daniel P. SUTHERLIN ◽  
Guy S. SALVESEN
Keyword(s):  
Active Form ◽  
Caspase 8 ◽  
Death Domain ◽  
Caspase Activation ◽  
Inhibitory Protein ◽  
Long Form ◽  
Initiator Caspases ◽  
Domain Protein ◽  
Enzyme Molecules

The first step in caspase activation is transition of the latent zymogen to an active form. For the initiator caspases, this occurs through dimerization of monomeric zymogens at an activating complex. Recent studies have suggested that FLIPL [FLICE-like inhibitory protein, long form; FLICE is FADD (Fas-associated death domain protein)-like interleukin-1β-converting enzyme], previously thought to act solely as an inhibitor of caspase-8 activation, can under certain circumstances function to enhance caspase activation. Using an in vitro induced-proximity assay, we demonstrate that activation of caspases-8 and -10 occurs independently of cleavage of either the caspase or FLIPL. FLIPL activates caspase-8 by forming heterodimeric enzyme molecules with substrate specificity and catalytic activity indistinguishable from those of caspase-8 homodimers. Significantly, the barrier for heterodimer formation is lower than that for homodimer formation, suggesting that FLIPL is a more potent activator of caspase-8 than is caspase-8 itself.

TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus

Blood ◽  
2004 ◽  
Vol 104 (1) ◽  
pp. 184-191 ◽  
Author(s):  
Wataru Matsuyama ◽  
Masuki Yamamoto ◽  
Ikkou Higashimoto ◽  
Ken-ichi Oonakahara ◽  
Masaki Watanabe ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Healthy Volunteers ◽  
Lupus Erythematosus ◽  
Laboratory Finding ◽  
Significant Negative Correlation ◽  
Trail Receptor ◽  
Death Domain ◽  
Systemic Lupus ◽  
Inhibitory Protein

Abstract Neutropenia is a common laboratory finding in systemic lupus erythematosus (SLE). However, the molecular mechanism of SLE neutropenia has not been fully explained. In this study, we examined whether TNF-related apoptosis-inducing ligand (TRAIL) is involved in the pathogenesis of SLE neutropenia using samples from SLE patients. Serum TRAIL levels in SLE patients with neutropenia were significantly higher than those of SLE patients without neutropenia and healthy volunteers. Serum TRAIL levels showed a significant negative correlation with neutrophil counts in SLE patients. The expression of TRAIL receptor 3 was significantly lower in SLE patients with neutropenia than in patients without neutropenia or in healthy volunteers. Treatment with glucocorticoids negated the decrease of TRAIL receptor 3 expression on neutrophils of SLE patients. TRAIL may accelerate neutrophil apoptosis of neutrophils from SLE patients, and autologous T cells of SLE patients, which express TRAIL on surface, may kill autologous neutrophils. Interferon gamma and glucocorticoid modulated the expression of TRAIL on T cells of SLE patients and also modulated the expression of cellular Fas-associating protein with death domain–like interleukin-1β–converting enzyme (FLICE)–inhibitory protein (cFLIP), an inhibitor of death receptor signaling, in neutrophils. Thus, our results provide a novel insight into the molecular pathogenesis of SLE neutropenia.

Reliability of Proposed Short Form of Illinois Test of Psycholinguistic Abilities

1978 ◽  
Vol 45 (3) ◽  
pp. 198-204 ◽  
Author(s):  
Ronald P. Maggiore
Keyword(s):  
Internal Consistency ◽  
Short Form ◽  
Full Length ◽  
Psychometric Instrument ◽  
Tests Of Significance ◽  
The Future ◽  
Administration Time

The reliability of the proposed short form of the Revised Illinois Test of Psycholinguistic Abilities (Newcomer & Hammill, 1974) was computed on data derived from 6 year old ITPA standardization test booklets. Measures of internal consistency and between forms reliability were obtained for both full length and short form scorings of single ITPA test administrations. Tests of significance yielded significantly lower measures on 10 of 12 subtests for the short form test when compared to the internal consistency of the full length test. The correlation between the two forms was significantly reduced in all cases when the part-whole correspondence was accounted for. The results were discussed in terms of their impact on the future use of the proposed short form as a psychometric instrument of questionable reliability. Suggestions were proposed for those concerned with reducing administration time.

scholarly journals Effects of Pathological Mutations on the Prion-Like Polymerisation of MyD88

2018 ◽  
Author(s):  
Ailís O’Carroll ◽  
Brieuc Chauvin ◽  
James Brown ◽  
Ava Meagher ◽  
Joanne Coyle ◽  
...  
Keyword(s):  
Single Molecule ◽  
Self Assembly ◽  
Point Mutations ◽  
Adaptor Protein ◽  
Full Length ◽  
Binary Response ◽  
Death Domain ◽  
Tir Domain ◽  
The Impact

AbstractA novel concept has emerged whereby the higher-order self-assembly of proteins provides a simple and robust mechanism for signal amplification. This appears to be a universal signalling mechanism within the innate immune system, where the recognition of pathogens or danger-associated molecular patterns need to trigger a strong, binary response within cells. Previously, multiple structural studies have been limited to single domains, expressed and assembled at high protein concentrations. We therefore set out to develop new in vitro strategies to characterise the behaviour of full-length proteins at physiological levels. In this study we focus on the adaptor protein MyD88, which contains two domains with different self-assembly properties: a TIR domain that can polymerise similarly to the TIR domain of Mal, and a Death Domain that has been shown to oligomerise with helical symmetry in the Myddosome complex. To visualize the behaviour of full-length MyD88 without purification steps, we use single-molecule fluorescence coupled to eukaryotic cell-free protein expression. These experiments demonstrate that at low protein concentration, only full-length MyD88 forms prion-like polymers. We also demonstrate that the metastability of MyD88 polymerisation creates the perfect binary response required in innate signalling: the system is silenced at normal concentrations but upstream signalling creates a “seed” that triggers polymerisation and amplification of the response. These findings pushed us to re-interpret the role of polymerisation in MyD88-related diseases and we studied the impact of disease-associated point mutations L93P, R196C and L252P/L265P at the molecular level. We discovered that all mutations completely block the ability of MyD88 to polymerise. We also confirm that L252P, a gain-of-function mutation, allows the MyD88 mutant to form extremely stable oligomers, even when expressed at low nanomolar concentrations. Thus, our results are consistent with and greatly add to the findings on the Myddosomes digital ‘all-or-none’ responses and the behaviour of the oncogenic mutation of MyD88.

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