Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS)

• Published in: Blood Vol. 108; no. 4; pp. 1320 - 1327
• Main Authors: Lobito, Adrian A., Kimberley, Fiona C., Muppidi, Jagan R., Komarow, Hirsh, Jackson, Adrianna J., Hull, Keith M., Kastner, Daniel L., Screaton, Gavin R., Siegel, Richard M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-08-2006; The Americain Society of Hematology; The American Society of Hematology
• Subjects: Animals; Apoptosis - genetics; Biological and medical sciences; Chlorocebus aethiops; COS Cells; Disease Models, Animal; Diseases of the osteoarticular system; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Familial Mediterranean Fever - genetics; Familial Mediterranean Fever - metabolism; Humans; Immunobiology; Inflammatory joint diseases; Medical sciences; Mice; Mice, Transgenic; NF-kappa B - metabolism; Point Mutation; Protein Folding; Protein Transport - genetics; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Signal Transduction - genetics; Human; Signal transduction; Oligomerization; Tumor necrosis factor; Pathogenesis; Tumor necrosis factor receptor 1; Diseases of the osteoarticular system; Familial recurrent polyseritis; Mutation; Endoplasmic reticulum; Genetic disease; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-11-006783

Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by 9 distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse “knock-in” model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes. Mutant receptors did not bind TNF and failed to function as dominant-negative inhibitors of TNFR1-induced apoptosis. Instead, TRAPS mutant TNFR1 formed abnormal disulfide-linked oligomers that failed to interact with wild-type TNFR1 molecules through the preligand assembly domain (PLAD) that normally governs receptor self-association. TRAPS mutant TNFR1 molecules were retained intracellularly and colocalized with endoplasmic reticulum (ER) markers. The capacity of mutant receptors to spontaneously induce both apoptosis and nuclear factor κB (NF-κB) activity was reduced. In contrast, the R92Q variant of TNFR1 behaved like the wild-type receptor in all of these assays. The inflammatory phenotype of TRAPS may be due to consequences of mutant TNFR1 protein misfolding and ER retention.