Shedding of mutant tumor necrosis factor receptor superfamily 1A associated with tumor necrosis factor receptor–associated periodic syndrome: Differences between cell types

Huggins, Mary L.; Radford, Paul M.; McIntosh, Richard S.; Bainbridge, Susan; Dickinson, Peter J.; Draper‐Morgan, Kelly‐Ann; Tighe, Patrick J.; Powell, Richard J.; Todd, Ian

doi:10.1002/art.20380

Cited by 71 publications

(74 citation statements)

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“…Peripheral blood leukocytes from TRAPS patients with T50M and T50K variants showed defective TNFRI shedding (3,17). However, it has recently been reported that variations in TNFRI shedding are not only related to the structural mutations in TNFRI, but may also depend on other cellular factors (16).…”

Section: Discussionmentioning

confidence: 96%

“…In recent studies, Huggins et al (16) and Todd et al (15) analyzed HEK 293 cells stably transfected with truncated WT TNFRI and TRAPS-associated TNFRI variants lacking the cytoplasmic regions and showed that the surface expression of the T50M variant was similar to that observed for the WT receptor. Moreover, the full-length T50M variant was also expressed on the cell surface, although at a lower level than that of the WT TNFRI.…”

Section: Discussionmentioning

confidence: 98%

“…In addition, the data obtained were based on fluorescence-activated cell sorting or enzymelinked immunosorbent assay analysis using monoclonal antibodies whose specificity for the mutated forms of TNFRI has not been carefully assessed, and biochemical analyses such as immunoblotting were not performed. In an attempt to overcome these difficulties, regulated expression of TNFRI in a tetracycline-regulated system has been tried; however, maximal levels of antibiotic were required to obtain high levels of gene expression (15,16). Despite these caveats, investigators in those studies have hypothesized (but not demonstrated) a gain of function with proinflammatory consequences for the TNFRI mutations (15,16).…”

mentioning

confidence: 99%

“…In an attempt to overcome these difficulties, regulated expression of TNFRI in a tetracycline-regulated system has been tried; however, maximal levels of antibiotic were required to obtain high levels of gene expression (15,16). Despite these caveats, investigators in those studies have hypothesized (but not demonstrated) a gain of function with proinflammatory consequences for the TNFRI mutations (15,16).…”

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confidence: 99%

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Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Yousaf¹,

Gould²,

Aganna³

et al. 2005

Arthritis & Rheumatism

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Objective. To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR-associated periodic syndrome (TRAPS).Methods. We cloned and expressed full-length wild-type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline-dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression.Results. We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline-controlled up-regulation of one TNFRI allele, either WT or mutant, caused downregulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF-B p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI.Conclusion. The T50K TRAPS-related variant is capable of sustaining inappropriate NF-B activation, resulting in persistent autoinflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up-regulating TNFRI expression may cause cellular activation through the NF-B signaling pathway.Tumor necrosis factor receptor-associated periodic syndrome (TRAPS; MIM no. 142680) is a dominantly inherited chronic inflammatory disorder caused by mutations in the extracellular domains of tumor necrosis factor receptor I (TNFRI), the gene for which is TNFRSF1A (1), and characterized by recurrent fevers and abdominal pain. The most common mutations involve cysteine residues, but several variants involving other residues have also been reported (1,2). More than 30 different pathogenic TNFRSF1A mutations have now been identified (see http://fmf.igh.cnrs.fr/infevers/ and ref.2), mostly located in either the first or second cysteine-rich N-terminal extracellular domain (CRD1 or CRD2) of TNFRSF1A (2,3). Impaired cleavage of the TNFRI (p55) ectodomain upon cellular activation has been demonstrated as a pathogenic mechanism in some but not all TNFRI variants (3-6) and did not relate to the severity of the phenotype (7,8).Biologic activities of TNF are mediated through 2 TNFRs, TNFRI and TNFRII (TNFR superfamily 1B

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Yousaf¹,

Gould²,

Aganna³

et al. 2005

Arthritis & Rheumatism

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“…The TNFR1 is present physiologically in both the soluble (sTNFR1) and membrane (mTNFR1) bound form, both of which are decreased in TRAPS patients [15][16][17][18][19][20]. These observations suggest either defective receptor shedding or defective trafficking of mutant receptors to the cell surface.…”

Section: Autoinflamamatory Diseases Linked To Disorders In Protein MImentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant

Siebert¹,

Amos²,

Fielding³

et al. 2005

Arthritis & Rheumatism

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Objective. Tumor necrosis factor receptorassociated periodic syndrome (TRAPS) is an autoinflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor superfamily 1A (TNFRSF1A). The purpose of this study was to describe a novel TNFRSF1A mutation (C43S) in a patient with TRAPS and to examine the effects of this TNFRSF1A mutation on tumor necrosis factor ␣ (TNF␣)-induced signaling in a patient-derived primary dermal fibroblast line.Methods. TNFRSF1A shedding from neutrophils was measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Primary dermal fibroblast lines were established from the patient with the C43S TRAPS mutation and from healthy volunteers. Activation of NF-B and activator protein 1 (AP-1) was evaluated by electrophoretic mobility shift assays. Cytokine production was measured by ELISA. Cell viability was measured by alamar blue assay. Apoptosis was measured by caspase 3 assay in the fibroblasts and by annexin V assay in peripheral blood mononuclear cells.Results. Activation-induced shedding of the TNFRSF1A from neutrophils was not altered by the C43S TRAPS mutation. TNF␣-induced activation of NF-B and AP-1 was decreased in the primary dermal fibroblasts with the C43S TNFRSF1A mutation. Nevertheless, the C43S TRAPS fibroblasts were capable of producing interleukin-6 (IL-6) and IL-8 in response to TNF␣. However, TNF␣-induced cell death and apoptosis were significantly decreased in the samples from the patient with the C43S TRAPS mutation.Conclusion. The C43S TNFRSF1A mutation results in decreased TNF␣-induced nuclear signaling and apoptosis. Our data suggest a new hypothesis, in that the C43S TRAPS mutation may cause the inflammatory phenotype by increasing resistance to TNF␣-induced apoptosis.

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Shedding of mutant tumor necrosis factor receptor superfamily 1A associated with tumor necrosis factor receptor–associated periodic syndrome: Differences between cell types

Cited by 71 publications

References 25 publications

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant

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