Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever

Manukyan, Gayane; Aminov, Rustam

doi:10.3389/fmicb.2016.00456

Cited by 80 publications

(84 citation statements)

References 89 publications

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“…Pyrin (also called MEFV, TRIM20 or marenostrin) is the founding member of the pyrin domain family of proteins. A number of mutations in human Pyrin have been reported and associated with the most common human autoinflammatory disease, Familial Mediterranean Fever (FMF), where the pathology is believed to be initiated by hyperactivation of Pyrin-Asc-caspase-1 inflammasomes [14,15,16]. Bacteria can also activate Pyrin inflammasomes.…”

Section: Introductionmentioning

confidence: 99%

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

et al. 2016

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Type III secretion systems (T3SS) are central virulence factors for many pathogenic Gram-negative bacteria, and secreted T3SS effectors can block key aspects of host cell signaling. To counter this, innate immune responses can also sense some T3SS components to initiate anti-bacterial mechanisms. The Yersinia pestis T3SS is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines IL-1β and IL-18, which are typically processed into their mature forms by active caspase-1 following inflammasome formation. Some effectors, like Y. pestis YopM, may block inflammasome activation. Here we show that YopM prevents Y. pestis induced activation of the Pyrin inflammasome induced by the RhoA-inhibiting effector YopE, which is a GTPase activating protein. YopM blocks YopE-induced Pyrin-mediated caspase-1 dependent IL-1β/IL-18 production and cell death. We also detected YopM in a complex with Pyrin and kinases RSK1 and PKN1, putative negative regulators of Pyrin. In contrast to wild-type mice, Pyrin deficient mice were also highly susceptible to an attenuated Y. pestis strain lacking YopM, emphasizing the importance of inhibition of Pyrin in vivo. A complex interplay between the Y. pestis T3SS and IL-1β/IL-18 production is evident, involving at least four inflammasome pathways. The secreted effector YopJ triggers caspase-8- dependent IL-1β activation, even when YopM is present. Additionally, the presence of the T3SS needle/translocon activates NLRP3 and NLRC4-dependent IL-1β generation, which is blocked by YopK, but not by YopM. Taken together, the data suggest YopM specificity for obstructing the Pyrin pathway, as the effector does not appear to block Y. pestis-induced NLRP3, NLRC4 or caspase-8 dependent caspase-1 processing. Thus, we identify Y. pestis YopM as a microbial inhibitor of the Pyrin inflammasome. The fact that so many of the Y. pestis T3SS components are participating in regulation of IL-1β/IL-18 release suggests that these effects are essential for maximal control of innate immunity during plague.

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Section: Introductionmentioning

confidence: 99%

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

et al. 2016

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“…As noted above, the majority of FMF-causing mutations are located in the B30.2 domain 72 . The PYD domain interacts with an adapter protein, apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), through a homotypic PYD-PYD interaction 73 .…”

Section: Recent Advances In Fmf and The Pyrin Inflammasomementioning

confidence: 84%

Genomics, Biology, and Human Illness

Oda

Kastner

2017

Rheumatic Disease Clinics of North America

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SYNOPSIS The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically-determined recurrent sterile inflammation, and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines such as IL-1 and TNF and intracellular cytokine signaling pathways have proven effective in many cases. Emerging next generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. In this review we will cover several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies.

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“…The following major points have been raised from the present case series: (a) using the molecular approach for FMF diagnosis, it is now obvious that the disease is clinically heterogeneous reflecting probably the complexity and multiplicity of pyrin functions;7 (b) contrary to the known conservative mutations clustered in exon 10 ( M694V , V726A , M680I , M694I ) and exon 2 ( E148Q ), the presence of R202Q in exon 2 further supports this mutation as disease-related in Greek patients with FMF; and most importantly, (c) although severe liver involvement is extremely rare in FMF cases, this possibility should be considered if there are recurrent episodes of unexplained severe liver impairment including remarkable jaundice accompanied by fever and in particular in regions like Mediterranean basin where HPFS are common as attested by our two cases who characterised by a significant delay of diagnosis.…”

Section: Discussionmentioning

confidence: 96%

Severe liver involvement in two patients with long-term history of fever: remember familial Mediterranean fever

et al. 2016

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Familial Mediterranean fever (FMF) is characterised by recurrent, self-limited fever attacks and serositis. Severe liver involvement has rarely been reported. We present two FMF cases of a 55-year-old man and a 20-year-old woman in whom the prevailing manifestations were recurrent unexplained episodes of anicteric hepatitis (man) and recurrent severe jaundice (woman). A long-term history of recurrent self-limited episodes of fever was also claimed in both. After exclusion of infectious, malignant, autoimmune, and liver and biliary diseases, a diagnosis of FMF as confirmed by molecular analysis was established. The patients started colchicine 1 mg/day with immediate resolution of symptoms. During follow-up, no new episodes of fever and exacerbation of liver biochemical parameters have been recorded for 5 and 1 years. Physicians must keep FMF in mind in patients with recurrent episodes of unexplained severe liver impairment and fever and especially in regions like Mediterranean basin where hereditary periodic fever syndromes are common.

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Update on Pyrin Functions and Mechanisms of Familial Mediterranean Fever

Cited by 80 publications

References 89 publications

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

Genomics, Biology, and Human Illness

Severe liver involvement in two patients with long-term history of fever: remember familial Mediterranean fever

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