Falling into TRAPS – receptor misfolding in the TNF receptor 1-associated periodic fever syndrome

Abstract

TNF receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disease caused by missense mutations in the TNF receptor 1 (TNFR1) gene. Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1. In the present review we discuss new findings describing aberrant trafficking and function of TNFR1 harbouring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding, and we suggest that TNFR1 might acquire novel functions in the endoplasmic reticulum, distinct from its role as a cell surface receptor. We also describe the clinical manifestations of TRAPS, current treatment regimens, and the widening array of patient mutations. IntroductionThe TNF-receptor associated periodic syndrome (TRAPS) is a dominantly inherited periodic fever syndrome characterised by prolonged episodic fevers, multiorgan involvement, and resistance to colchicine. Over 40 missense mutations in TNF receptor 1 (TNFR1), the prototypical proinflammatory receptor, have been associated with TRAPS. In the present review we discuss recent evidence that the unifying molecular defect in TRAPS-associated mutant TNFR1 is receptor misfolding and retention in the endoplasmic reticulum (ER). This finding constitutes a novel mechanism of receptor misbehaviour in genetic disease and suggests hitherto unexpected functions for intracellularly retained receptors in promoting inflammation. Periodic fevers and TRAPSThe periodic fevers are a group of disorders characterised by unprovoked attacks of fever and localised inflammation that can affect multiple organ systems [1]. There are several periodic fever syndromes that are inherited in a recessive manner, such as familial Mediterranean fever (FMF) caused by mutations in the gene encoding the neutrophil-specific protein Pyrin [2]. Most evidence currently suggests that pyrin negatively regulates the production of IL-1β -a major proinflammatory cytokine of the innate immune response [3]. IL-1β is generated from its proform via cleavage by caspase-1, which occurs in a specialised IL-1 activating protein complex termed the inflammasome [4][5][6]. FMF-associated mutations in pyrin are thought to exert less inhibition of IL-1β processing [7]. Another such recessive disease is hyperimmunoglobulinemia-D with periodic fever syndrome, which arises due to mutations in mevalonate kinase -a key enzyme in cholesterol biosynthesis and the synthesis of nonsterol isoprenoid molecules [8,9]. The exact molecular basis for the disease resulting from these mutations, however, remains unclear.The molecular basis of two groups of dominant periodic fever syndrome has been identified. Dominant mutations in the CIAS1 gene are associated with a heterogeneous group of inflammatory conditions encompassing Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and the neonatal onset multisystem inflamma...

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

“…Treatment with TNF-blocking agents should cause a dramatic decrease in symptoms if decreased shedding of TNFR1 were the sole abnormality in TRAPS. However, TNF blockade does not always induce complete remission or normalization of acutephase reactants in TRAPS (4,(13)(14)(15). All TRAPS-associated mutations in TNFR1 studied to date that are not found in the general population profoundly disrupt receptor trafficking, resulting in intracellular retention of mutant receptors in the endoplasmic reticulum (ER) (16,17), likely because of abnormal oligomerization of mutant receptors through nonphysiological disulfide bonds.…”

“…Missense mutations in TNFRSF1A, the gene encoding TNFR1, are the cause of the autosomal dominant autoinflammatory disease, TNFR-associated periodic syndrome (TRAPS) (3,4). This syndrome is characterized by recurrent prolonged episodes of fever and inflammation, which occur either spontaneously or after minor triggers.…”

“…Symptoms include fever, serositis, migratory rashes, and myalgia associated with inflammatory fasciitis. TRAPS also can be complicated by systemic amyloidosis (4). TRAPS is part of an emerging group of diseases termed "autoinflammatory" that involve abnormal activation of the innate immune system in the absence of autoantibodies or autoreactive T cells.…”

A monoallelic double mutation as a cause for TNF receptor-associated periodic fever syndrome

“…Most TRAPS-associated mutations have been identified to be of the missense type and are located predominantly within the first or second cysteine-rich N-terminal extracellular domain (CRD1 and CRD2) of the receptor [6,13]. Recent studies concentrate on the mechanism of TRAPS signaling pathways and discuss new findings describing aberrant trafficking and function of TNFRSF1A harboring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding [13].…”

“…Recent studies concentrate on the mechanism of TRAPS signaling pathways and discuss new findings describing aberrant trafficking and function of TNFRSF1A harboring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding [13]. It is suggested that TNFRSF1A might acquire novel functions in the endoplasmatic reticulum, distinct from its role as a cell surface receptor.…”