scholarly journals Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling

2009 ◽  
Vol 419 (1) ◽  
pp. 185-194 ◽  
Author(s):  
Aurélie Rossin ◽  
Mathieu Derouet ◽  
Fadi Abdel-Sater ◽  
Anne-Odile Hueber
Keyword(s):  
Protein Trafficking ◽  
Tumour Necrosis ◽  
Signal Transmission ◽  
Tumour Necrosis Factor Receptor ◽  
Trail Receptor ◽  
Lipid Modification ◽  
Death Domain ◽  
Protein Palmitoylation ◽  
Necrosis Factor ◽  
Tnf Tumour Necrosis Factor

S-palmitoylation is a lipid modification that regulates membrane–protein association and influences protein trafficking, stability or aggregation, thus playing an important role in protein signalling. We previously demonstrated that the palmitoylation of Fas, one of the DD (death domain)-containing members of the TNFR [TNF (tumour necrosis factor) receptor] superfamily, is essential for the redistribution of this receptor into lipid rafts, an obligatory step for the death signal transmission. Here we investigate the requirement of protein palmitoylation in the activities of other DD-containing death receptors. We show that DR4 is palmitoylated, whereas DR5 and TNFR1 are not. Furthermore, DR4 palmitoylation is required for its raft localization and its ability to oligomerize, two essential features in TRAIL (TNF-related apoptosis-inducing ligand)-induced death signal transmission.

scholarly journals The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD)

2009 ◽  
Vol 69 (6) ◽  
pp. 1243-1246 ◽  
Author(s):  
Jennifer J Pointon ◽  
David Harvey ◽  
Tugce Karaderi ◽  
Louise H Appleton ◽  
Claire Farrar ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Candidate Gene ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Receptor Type ◽  
Tumour Necrosis Factor Receptor ◽  
Death Domain ◽  
Meta Analyses ◽  
Necrosis Factor

ObjectiveTo replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1.MethodsFirstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls.ResultsThe association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified.ConclusionsThe region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.

the tumour necrosis factor receptor-associated periodic syndrome: current concepts

2005 ◽  
Vol 7 (22) ◽  
pp. 1-18 ◽  
Author(s):  
silvia stojanov ◽  
michael f. mcdermott
Keyword(s):  
Tumour Necrosis Factor ◽  
Lupus Erythematosus ◽  
Tumour Necrosis ◽  
Periodic Fever ◽  
Blood Levels ◽  
Tumour Necrosis Factor Receptor ◽  
Periodic Syndrome ◽  
Death Domain ◽  
Rational Form ◽  
Necrosis Factor

the tumour necrosis factor receptor (tnfr)-associated periodic syndrome (traps) is an autosomal dominant, multisystemic, autoinflammatory disorder caused by mutations in the tnfr1 gene (tnfrsf1a). traps seems to be the most common hereditary periodic fever (hpf) syndrome in some western populations, and the second most prevalent hpf worldwide, behind familial mediterranean fever (fmf). the proteins involved in susceptibility to traps (tnfrsf1a) and fmf (pyrin) are both members of the death-domain-fold superfamily. mutations affecting these proteins might cause dysregulation of innate immune responses, with a propensity to autoinflammation. most traps patients have reduced blood levels of soluble tnfrsf1a between attacks, with an inappropriately small increase during bouts of fever. the pathogenesis of the ‘hyperinflammatory state’ in traps has been variously ascribed to a shedding defect of tnfrsf1a from the cell surface resulting in increased tnf inflammatory signalling, or impaired tnf apoptotic signalling. some low-penetrance tnfrsf1a variants also contribute to the clinical phenotype in individuals carrying other hpf-associated mutations, and have been reported in several disorders such as behçet's disease and systemic lupus erythematosus. synthetic anti-tnf agents provide a rational form of therapy for traps, and have been shown to delay or indeed prevent development of systemic amyloidosis (aa type), a life-threatening complication in this condition.

Host response to cytoadherence in Plasmodium falciparum

2008 ◽  
Vol 36 (2) ◽  
pp. 221-228 ◽  
Author(s):  
Srabasti J. Chakravorty ◽  
Katie R. Hughes ◽  
Alister G. Craig
Keyword(s):  
Plasmodium Falciparum ◽  
Tumour Necrosis ◽  
Host Response ◽  
Severe Disease ◽  
Signalling Pathways ◽  
Malarial Infection ◽  
Extensive Information ◽  
Adhesive Interactions ◽  
Necrosis Factor ◽  
Tnf Tumour Necrosis Factor

Cytoadherence of PRBCs (Plasmodium falciparum-infected red blood cells) to host endothelium has been associated with pathology in severe malaria, but, despite extensive information on the primary processes involved in the adhesive interactions, the mechanisms underlying the disease are poorly understood. Endothelial cells have the ability to mobilize immune and pro-adhesive responses when exposed to both PRBCs and TNF (tumour necrosis factor). In addition, there is also an up-regulation by PRBCs and TNF and a concurrent down-regulation of a range of genes involved in inflammation and cell death, by PRBCs and TNF. We propose that the balance between positive and negative regulation will contribute to endothelial pathology during malarial infection. Apposition of PRBCs has been shown by a number of groups to activate signalling pathways. This is dependent, at least in part, on the cytoadherence characteristics of the invading isolate, such that the avidity of the PRBC for the receptor on host endothelium is proportional to the level of activation of the signalling pathways. An understanding of the post-adhesive processes produced by cytoadherence may help us to understand the variable pathology seen in malaria and to design appropriate therapies to alleviate severe disease.

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