Gain-of-Function Pyrin Mutations Induce NLRP3 Protein-Independent Interleukin-1β Activation and Severe Autoinflammation in Mice

Chae, Jae Jin; Cho, Young-Hun; Lee, Geun‐Shik; Cheng, Jun; Liu, P. Paul; Feigenbaum, Lionel; Katz, Stephen I.; Kastner, Daniel L.

doi:10.1016/j.immuni.2011.02.020

Cited by 411 publications

(404 citation statements)

References 34 publications

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“…We focused on TRIM20 as a TRIM strongly induced by IFN-γ (Carthagena et al, 2009;Chae et al, 2011). We confirmed that TRIM20 expression was responsive to IFN-γ in our system and tested its kinetics and dose-response (Fig.…”

Section: Trim20 Induces Autophagysupporting

confidence: 61%

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

Kimura¹,

Jain²,

Choi³

et al. 2015

J Exp Med

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Section: Trim20 Induces Autophagysupporting

confidence: 61%

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

Kimura¹,

Jain²,

Choi³

et al. 2015

J Exp Med

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“…As a consequence, an inappropriate full-blown inflammation occurs. The activation of IL-1β is mediated by an inflammatory trigger leading to the induction of an inflammasome [27]. TNFalpha plays a role in the mediation of the inflammatory cascade.…”

Section: Discussionmentioning

confidence: 99%

The role of adalimumab in the treatment of colchicine-resistant familial mediterranean fever: a case report

Issa

Noureddine

2016

Int Arch Med

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Familial Mediterranean fever (FMF) is an autosomal recessive inherited disorder. Articular manifestations are the second most common presentation in FMF patients after abdominal pain. Colchicine remains the gold standard of therapy for the different aspects of the disease. However, about 5-15% of patients experience resistance to colchicine. Therefore, physicians were encouraged to try different medications and treatment modalities. Biologic agents were used in several FMF patients with various clinical presentations including articular involvement. In the majority of those, there was a good clinical response with improvement in the quality of life. Adalimumab is an anti-TNF alpha agent used conventionally in inflammatory bowel disease and rheumatologic disorders. To date only five cases were reported in the literature using adalimumab for severe refractory FMF.Our case report details a young female with severe disabling colchicine-resistant FMF associated with significant articular inflammation. She was treated with adalimumab with remarkable clinical improvement and complete response.

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“…Activated inflammasomes are visible as microscopic 'specks' within the cytosol and structural studies have shown that they can polymerize into large oligomers with potentially thousands of subunits [39]. Gain-of-function mutations in the NLRP3 gene are cause de novo and inherited autoinflammatory diseases collectively known as cryopyrin-associated periodic syndromes (CAPS) [40]. Pathogenic mutations, predominantly found in exon 3, affect the NBD within NLRP3 leading to spontaneous oligomerization and a reduced requirement for the second stimulus, ATP, for IL-1secretion after activation by innate immune stimuli [41].…”

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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Gain-of-Function Pyrin Mutations Induce NLRP3 Protein-Independent Interleukin-1β Activation and Severe Autoinflammation in Mice

Cited by 411 publications

References 34 publications

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity

The role of adalimumab in the treatment of colchicine-resistant familial mediterranean fever: a case report

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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