scholarly journals Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra45-332ra45 ◽  
Author(s):  
Seth L. Masters ◽  
Vasiliki Lagou ◽  
Isabelle Jéru ◽  
Paul J. Baker ◽  
Lien Van Eyck ◽  
...  
Keyword(s):  
Autoinflammatory Disease ◽  
Neutrophilic Dermatosis ◽  
Binding Motif ◽  
Inflammasome Activation ◽  
Childhood Onset ◽  
Gene Encoding ◽  
Acute Phase Reactants ◽  
Spry Domain ◽  
Mediterranean Fever ◽  
Bacterial Effectors

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridiumdifficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.

scholarly journals Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation

2016 ◽  
Vol 113 (50) ◽  
pp. 14384-14389 ◽  
Author(s):  
Hanne Van Gorp ◽  
Pedro H. V. Saavedra ◽  
Nathalia M. de Vasconcelos ◽  
Nina Van Opdenbosch ◽  
Lieselotte Vande Walle ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Autoinflammatory Disease ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Microtubule Assembly ◽  
Inflammasome Activation ◽  
Wild Type ◽  
Peripheral Blood Mononuclear ◽  
Mouse Macrophages ◽  
Mediterranean Fever

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.

scholarly journals A novel Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever

2017 ◽  
Vol 76 (12) ◽  
pp. 2085-2094 ◽  
Author(s):  
Fiona Moghaddas ◽  
Rafael Llamas ◽  
Dominic De Nardo ◽  
Helios Martinez-Banaclocha ◽  
Juan J Martinez-Garcia ◽  
...  
Keyword(s):  
Cell Death ◽  
Familial Mediterranean Fever ◽  
Clinical Features ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Cytokine Profile ◽  
Neutrophilic Dermatosis ◽  
Binding Motif ◽  
Control Serum ◽  
Mediterranean Fever

ObjectivePyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) is a recently described monogenic autoinflammatory disease. The causal p.S242R MEFV mutation disrupts a binding motif of the regulatory 14-3-3 proteins within pyrin. Here, we investigate a family with clinical features consistent with PAAND in whom the novel p.E244K MEFV mutation, located in the +2 site of the 14-3-3 binding motif in pyrin, has been found.MethodsMultiplex cytokine analyses were performed on p.E244K patient and control serum. Peripheral blood mononuclear cells were stimulated ex vivo with lipopolysaccharide (LPS). In vitro, inflammasome complex formation was evaluated by flow cytometry of Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) specks. Interleukin-1β (IL-1β) and IL-18 production was quantified by ELISA. The ability of the p.E244K pyrin mutation to interact with 14-3-3 was assessed by immunoprecipitation.ResultsPAAND p.E244K patient serum displayed a different cytokine profile compared with patients with Familial Mediterranean Fever (FMF). In overexpression models, p.E244K pyrin was associated with decreased 14-3-3 binding and increased ASC speck formation. THP-1 monocytes expressing PAAND pyrin mutations demonstrated spontaneous caspase-1-dependent IL-1β and IL-18 secretion, as well as cell death, which were significantly greater than those of wild-type and the FMF-associated mutation p.M694V.ConclusionIn PAAND, disruption of the +2 position of a 14-3-3 binding motif in pyrin results in its constitutive activation, with spontaneous production of IL-1β and IL-18, associated with inflammatory cell death. The altered serum cytokine profile may explain the different clinical features exhibited by PAAND patients compared with those with FMF.

scholarly journals Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation

2016 ◽  
Vol 113 (33) ◽  
pp. E4857-E4866 ◽  
Author(s):  
Wenqing Gao ◽  
Jieling Yang ◽  
Wang Liu ◽  
Yupeng Wang ◽  
Feng Shao
Keyword(s):  
Bone Marrow ◽  
Rho Gtpases ◽  
Autoinflammatory Disease ◽  
Bacterial Virulence ◽  
Bacterial Toxins ◽  
Microtubule Dynamics ◽  
Inflammasome Activation ◽  
Complex Mechanism ◽  
Site Specific ◽  
Mediterranean Fever

Pyrin, encoded by theMEFVgene, is best known for its gain-of-function mutations causing familial Mediterranean fever (FMF), an autoinflammatory disease. Pyrin forms a caspase-1–activating inflammasome in response to inactivating modifications of Rho GTPases by various bacterial toxins or effectors. Pyrin-mediated innate immunity is unique in that it senses bacterial virulence rather than microbial molecules, but its mechanism of activation is unknown. Here we show that Pyrin was phosphorylated in bone marrow-derived macrophages and dendritic cells. We identified Ser-205 and Ser-241 in mouse Pyrin whose phosphorylation resulted in inhibitory binding by cellular 14-3-3 proteins. The two serines underwent dephosphorylation upon toxin stimulation or bacterial infection, triggering 14-3-3 dissociation, which correlated with Pyrin inflammasome activation. We developed antibodies specific for phosphorylated Ser-205 and Ser-241, which confirmed the stimuli-induced dephosphorylation of endogenous Pyrin. Mutational analyses indicated that both phosphorylation and signal-induced dephosphorylation of Ser-205/241 are important for Pyrin activation. Moreover, microtubule drugs, including colchicine, commonly used to treat FMF, effectively blocked activation of the Pyrin inflammasome. These drugs did not affect Pyrin dephosphorylation and 14-3-3 dissociation but inhibited Pyrin-mediated apoptosis-associated Speck-like protein containing CARD (ASC) aggregation. Our study reveals that site-specific (de)phosphorylation and microtubule dynamics critically control Pyrin inflammasome activation, illustrating a fine and complex mechanism in cytosolic immunity.

Familial Mediterranean fever: the molecular pathways from stress exposure to attacks

Rheumatology ◽  
2020 ◽  
Vol 59 (12) ◽  
pp. 3611-3621
Author(s):  
Cengiz Korkmaz ◽  
Döndü U Cansu ◽  
Güven Barış Cansu
Keyword(s):  
Familial Mediterranean Fever ◽  
Autoinflammatory Disease ◽  
Inflammasome Activation ◽  
Molecular Pathways ◽  
Stress Exposure ◽  
Sympathoadrenal System ◽  
Mediterranean Fever ◽  
System Activation ◽  
New Perspective ◽  
Stress Mediators

Abstract FMF is an autoinflammatory disease characterized by recurrent attacks and increased IL-1 synthesis owing to activation of the pyrin inflammasome. Although knowledge of the mechanisms leading to the activation of pyrin inflammasome is increasing, it is still unknown why the disease is characterized by attack. The emergence of FMF attacks after emotional stress and the induction of attacks with metaraminol in previous decades suggested that stress-induced sympathoadrenal system activation might play a role in inflammasome activation and triggering attacks. In this review, we will review the possible molecular mechanism of stress mediators on the inflammation pathway and inflammasome activation. Studies on stress mediators and their impact on inflammation pathways will provide a better understanding of stress-related exacerbation mechanisms in both autoinflammatory and autoimmune diseases. This review provides a new perspective on this subject and will contribute to new studies.

scholarly journals Clostridium difficile Toxin B activates the NLRP3 inflammasome in human macrophages, demonstrating a novel regulatory mechanism for the Pyrin inflammasome

2021 ◽  
Author(s):  
Matthew Stephen James Mangan ◽  
Friederike Gorki ◽  
Karoline Krause ◽  
Alexander Heinz ◽  
Thomas Ebert ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Nlrp3 Inflammasome ◽  
Mefv Gene ◽  
Neutrophilic Dermatosis ◽  
Type I ◽  
Gene Encoding ◽  
Pathogen Virulence ◽  
Clostridioides Difficile ◽  
Mediterranean Fever ◽  
Clostridium Difficile Toxin B

Pyrin is a cytosolic immune sensor that forms an inflammasome when bacterial virulence factors inhibit RhoA, triggering the release of inflammatory cytokines, including IL-1β. Gain of function mutations in the MEFV gene encoding Pyrin cause auto-inflammatory disorders, such as familial Mediterranean fever (FMF) and Pyrin associated auto-inflammation with Neutrophilic Dermatosis (PAAND). To precisely define the role of Pyrin in detecting pathogen virulence factors in relevant human immune cells, we investigated how the Pyrin inflammasome response was initiated and regulated in monocyte-derived macrophages (hMDM) compared to human monocytes. Unlike monocytes and murine macrophages, we determined that hMDM failed to activate Pyrin in response to known Pyrin activators Clostridioides difficile (C. difficile) toxins A or B (TcdA or TcdB). In contrast, TcdB activated the NLRP3 inflammasome in hMDM. Notably, we ascertained that the Pyrin inflammasome response could be re-enabled in hMDM by prolonged priming with either LPS or type I or II interferons, and required an increase in Pyrin expression. These data demonstrate an unexpected redundancy in detecting these toxins by inflammasome sensors.

scholarly journals SAT0527 COMBINED EFFECT OF COMMON VARIANTS IN EXON 2 OR EXON 3 AND A PATHOGENIC MUTATION IN EXON 10 OF THE MEDITERRANEAN FEVER GENE ON INFLAMMASOME ACTIVATION IN JAPANESE PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1221.2-1221
Author(s):  
T. Koga ◽  
Y. Endo ◽  
K. Furukawa ◽  
K. Agematsu ◽  
A. Yachie ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Japanese Patients ◽  
Pathogenic Mutation ◽  
Inflammasome Activation ◽  
Combined Effects ◽  
Common Variants ◽  
Thoracic Pain ◽  
Exon 2 ◽  
Mediterranean Fever ◽  
Exon 10

Background:Familial Mediterranean fever (FMF) is an autoinflammatory disease that is caused by Mediterranean fever (MEFV) gene mutations. It is characterized by recurrent and self-limiting febrile attacks within a short period. Although the pathologic significance ofMEFVexon 2 or exon 3 common variants in patients with FMF is modest and these variants are usually associated with less severe clinical presentations of FMF (1, 2), their combined effects with pathogenic mutation in exon 10 remain to be evaluated.Objectives:To determine the combined effect of common variants on clinical manifestations and inflammasome activity, we compared the clinical and laboratory characteristics between the coexistence and non-coexistence ofMEFVexon 2 or exon 3 variants in patients with FMF that had a heterozygousMEFVexon 10 mutation.Methods:We excluded patients with FMF that had twoMEFVexon 10 mutations in one or more alleles and those withMEFVvariants in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygousMEFVexon 10 mutation, and they were divided into the groups with and withoutMEFVexon 2 or exon 3 variants of 34 and 97, respectively. All enrolled patients had only a heterozygous M694I mutation in exon 10 of theMEFVgene. We measured serum IL-18 levels at remission without febrile attacks in the groups with and withoutMEFVexon 2 or exon 3 variants of 9 and 31, respectively.Results:In the univariate analysis, the group with variants in exon 2 or exon 3 had significantly earlier onset (16.0 years v.s. 20.5 years, p = 0.04), a higher percentage of thoracic pain with febrile attacks (68% v.s. 44%, p = 0.02), a higher frequency of attack (1.0/month v.s. 0.5/month, p = 0.02), and a higher IL-18 level in the serum at remission (606.3 pg/ml v.s. 168.4 pg/ml, p = 0.04, Figure 1) compared to the group without these variants. Importantly, multivariate analyses showed that the coexistence ofMEFVexon 2 or exon 3 variants and an exon 10 mutation was independently and significantly associated with earlier onset of FMF (p = 0.049) and thoracic pain (p = 0.03).Figure 1.Conclusion:Our results suggest that the coexistence ofMEFVexon 2 or exon 3 variants and aMEFVexon 10 mutation has combined effects on inflammasome activation in the Japanese population.References:[1]Migita K, Uehara R, Nakamura Y, et al. Familial Mediterranean fever in Japan. Medicine (Baltimore). 2012 Nov;91(6):337-43.[2]Shinar Y, Livneh A, Langevitz P, Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000;27(7):1703.Disclosure of Interests:None declared

scholarly journals A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling

2010 ◽  
Vol 207 (12) ◽  
pp. 2569-2579 ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Zhenghua Luo ◽  
Michelle K. Manske ◽  
Tammy Price-Troska ◽  
Steven C. Ziesmer ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Novel Mutation ◽  
B Cell Development ◽  
Signaling Cascades ◽  
Binding Motif ◽  
Wild Type ◽  
Immunoglobulin Production ◽  
Gene Encoding ◽  
Non Hodgkin Lymphoma

The cytokine B cell activating factor (BAFF) and its receptor, BAFF receptor (BAFF-R), modulate signaling cascades critical for B cell development and survival. We identified a novel mutation in TNFRSF13C, the gene encoding human BAFF-R, that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma. This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif. Signaling through this mutant BAFF-R results in increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type (WT) BAFF-R. This correlates with increased TRAF2, TRAF3, and TRAF6 recruitment to His159Tyr BAFF-R. In addition, we document a requirement for TRAF6 in WT BAFF-R signaling. Together, these data identify a novel lymphoma-associated mutation in human BAFF-R that results in NF-κB activation and reveals TRAF6 as a necessary component of normal BAFF-R signaling.

scholarly journals The Synechococcus Strain PCC 7942glnN Product (Glutamine Synthetase III) Helps Recovery from Prolonged Nitrogen Chlorosis

2000 ◽  
Vol 182 (19) ◽  
pp. 5615-5619 ◽  
Author(s):  
Jörg Sauer ◽  
Ulrike Dirmeier ◽  
Karl Forchhammer
Keyword(s):  
Glutamine Synthetase ◽  
Transcriptional Start Site ◽  
Binding Motif ◽  
Class Iii ◽  
Wild Type ◽  
Cloning And Sequencing ◽  
Gene Encoding ◽  
Low Concentrations ◽  
Synechococcus Strain ◽  
Pcc 7942

ABSTRACT We report the cloning and sequencing of the glnN gene encoding a class III glutamine synthetase from the cyanobacteriumSynechococcus strain PCC 7942. Mapping of the transcriptional start site revealed a DNA sequence in the promoter region that resembles an imperfect NtcA binding motif. Expression ofglnN is impaired in NtcA- and PII-deficient mutants. The only parameter which was negatively affected in theglnN mutant compared to the wild type was the recovery rate of prolonged nitrogen-starved cells with low concentrations of combined nitrogen.

scholarly journals Abdominal syndrome in monogenic autoinflammatory disease – is it just a familial Mediterranean fever?

2020 ◽  
Vol 14 (4) ◽  
pp. 144-149
Author(s):  
S. O. Salugina ◽  
E. S. Fedorov ◽  
N. G. Volf
Keyword(s):  
Familial Mediterranean Fever ◽  
Autoinflammatory Disease ◽  
Bowel Perforation ◽  
Interleukin 1 ◽  
Diagnostic Features ◽  
Peritoneal Adhesions ◽  
Strict Adherence ◽  
Surgical Interventions ◽  
Abdominal Symptoms ◽  
Mediterranean Fever

Gastrointestinal (GI) manifestations, such as abdominal pain, nausea, vomiting, and diarrhea, are common autoinflammatory disease (AID) symptoms. The abdominal symptomatology reflecting serositis is one of the most important classification and diagnostic criteria for the classic monogenic AID (MAID) – familial Mediterranean fever (FMF). Failure to timely diagnose FMF frequently leads to unjustified surgical interventions. Other periodic fevers may also present as abdominal symptoms; however, the latter are outside their diagnostic features. These diseases include, first of all, tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Interleukin 1 (IL1) inhibitors serve as the major targeted drugs for the treatment of TRAPS. Russia has registered the IL1 inhibitor canakinumab that prevents the development of organ damages, including those in the GI tract. The paper describes a clinical case of the classic manifestations of TRAPS (fever, rash, periorbital edema, arthritis, and elevated levels of acutephase inflammatory markers) concurrent with severe abdominalgia during attacks and with the development of severe peritoneal adhesions, which led to bowel perforation and emergency surgical intervention. The prolonged persistence of inflammatory attacks before the initiation of therapy, as well as violation of the IL1 inhibitor administration regimen facilitated the development of an urgent exacerbation. Thus, TRAPS should be included in the differential diagnostic circle for patients with severe gastrointestinal manifestations characterized by an attack-like course. These patients need timely prescription of targeted therapy, strict adherence to the dosing and intervals between drug administrations, and careful monitoring to prevent serious complications with the visceral organs, including the gastrointestinal tract, and their immediate correction.

scholarly journals Crystal Structures of the BlaI Repressor from Staphylococcus aureus and Its Complex with DNA: Insights into Transcriptional Regulation of the bla and mec Operons

2005 ◽  
Vol 187 (5) ◽  
pp. 1833-1844 ◽  
Author(s):  
Martin K. Safo ◽  
Qixun Zhao ◽  
Tzu-Ping Ko ◽  
Faik N. Musayev ◽  
Howard Robinson ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dna Binding ◽  
Crystal Structures ◽  
Double Helix ◽  
Free Form ◽  
Binding Motif ◽  
Dimerization Domain ◽  
Gene Encoding ◽  
Dna Binding Sites ◽  
Dna Double Helix

ABSTRACT The 14-kDa BlaI protein represses the transcription of blaZ, the gene encoding β-lactamase. It is homologous to MecI, which regulates the expression of mecA, the gene encoding the penicillin binding protein PBP2a. These genes mediate resistance to β-lactam antibiotics in staphylococci. Both repressors can bind either bla or mec DNA promoter-operator sequences. Regulated resistance genes are activated via receptor-mediated cleavage of the repressors. Cleavage is induced when β-lactam antibiotics bind the extramembrane sensor of the sensor-transducer signaling molecules, BlaR1 or MecR1. The crystal structures of BlaI from Staphylococcus aureus, both in free form and in complex with 32 bp of DNA of the mec operator, have been determined to 2.0- and 2.7-Å resolutions, respectively. The structure of MecI, also in free form and in complex with the bla operator, has been previously reported. Both repressors form homodimers, with each monomer composed of an N-terminal DNA binding domain of winged helix-turn-helix topology and a C-terminal dimerization domain. The structure of BlaI in complex with the mec operator shows a protein-DNA interface that is conserved between both mec and bla targets. The recognition helix α3 interacts specifically with the conserved TACA/TGTA DNA binding motif. BlaI and, probably, MecI dimers bind to opposite faces of the mec DNA double helix in an up-and-down arrangement, whereas MecI and, probably, BlaI dimers bind to the same DNA face of bla promoter-operator DNA. This is due to the different spacing of mec and bla DNA binding sites. Furthermore, the flexibility of the dimeric proteins may make the C-terminal proteolytic cleavage site more accessible when the repressors are bound to DNA than when they are in solution, suggesting that the induction cascade involves bound rather than free repressor.

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