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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1320-1327.
Prepublished online as a Blood First Edition Paper on May 9, 2006; DOI 10.1182/blood-2005-11-006783.
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IMMUNOBIOLOGY
Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS)
Adrian A. Lobito,
Fiona C. Kimberley,
Jagan R. Muppidi,
Hirsh Komarow,
Adrianna J. Jackson,
Keith M. Hull,
Daniel L. Kastner,
Gavin R. Screaton, and
Richard M. Siegel
From the Immunoregulation Unit, Autoimmunity Branch, and Inflammatory Biology Section, Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD; Department of Pharmacology, Toxicology, & Therapeutics, University of Kansas Medical Center, Kansas City; and Hammersmith Hospital, Imperial College London, United Kingdom.
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  B (NF-B) 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.
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