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Int. J. Mol. Sci. 2016, 17(5), 725; doi:10.3390/ijms17050725

The Relationship between NALP3 and Autoinflammatory Syndromes

Rheumatology Fellows at University Hospitals Case Medical Center, Cleveland, OH 44106-5076, USA
Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, 2061 Cornell Road, Cleveland, OH 44106-5076, USA
Author to whom correspondence should be addressed.
Academic Editor: Irmgard Tegeder
Received: 17 March 2016 / Revised: 6 May 2016 / Accepted: 6 May 2016 / Published: 13 May 2016
(This article belongs to the Collection Feature Annual Reviews in Molecular Sciences)
View Full-Text   |   Download PDF [2376 KB, uploaded 13 May 2016]   |  


The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome, which is required for synthesis of interleukin-1β, has been implicated in the pathogenesis of several autoinflammatory syndromes. This review of the literature summarizes the interconnectedness of NALP3 inflammasome with some of these disorders. Familial Mediterranean fever results from a mutation in the Mediterranean fever (MEFV) gene, which encodes the pyrin protein. Previous study results suggest that pyrin suppresses caspase-1 activation, perhaps by competing for the adaptor protein, termed, pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ACS) which therefore interferes with NALP3 inflammasome activation. The nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing-3 (NALP3) inflammasome is constitutively activated in cryopyrin-associated periodic syndromes due to gain-of-function mutations resulting from point mutations within the neuronal apoptosis inhibitor protein/class 2 transcription factor/heterokaryon incompatibility/telomerase-associated protein-1 (NACHT) domain of the NALP3 protein. Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is caused by mutations in the genes encoding proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1). These PSTPIP1 mutants are thought to bind to pyrin causing an increase in the pyrin domain of apoptosis/speck-like protein containing a caspase-recruitment domain (ASC) pyroptosome assembly leading to procaspase-1 recruitment and therefore its activation. Hyperimmunoglublinemia D syndrome is caused by mevalonate kinase (MVK) deficiency, which may be affected by protein accumulation that leads to NALP3 inflammasome activation. Tumor necrosis factor receptor–associated periodic syndrome is associated with mutations in the tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene which decreases the level of soluble tumor necrosis factor receptor-1 (TNFR1) leading to neutralization of tumor necrosis factor (TNF)-α. In general, these autoinflammatory disorders have shown a clinical response to interleukin-1 (IL-1) antagonists, suggesting that the NALP3 inflammasome serves a critical role in their pathogenesis. View Full-Text
Keywords: NALP3 inflammasome; interleukin IL-1β; autoinflammatory syndromes NALP3 inflammasome; interleukin IL-1β; autoinflammatory syndromes

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Campbell, L.; Raheem, I.; Malemud, C.J.; Askari, A.D. The Relationship between NALP3 and Autoinflammatory Syndromes. Int. J. Mol. Sci. 2016, 17, 725.

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