The immunological function of familial Mediterranean fever disease protein Pyrin

Yang, Jia Lin; Xu, Hao; Shao, Feng

doi:10.1007/s11427-014-4758-3

Cited by 31 publications

(27 citation statements)

References 57 publications

(20 reference statements)

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“…We cannot fully exclude the possibility that impact on translocation of other molecules by YopK and YopE [11,26,27,28,29] could be a factor in our observations. In contrast, IL-1β induced by the ΔYopM strain is fully dependent upon the presence of Pyrin, similarly to a Burkholderia cenocepacia strain (JRL2) that lacks a functional T3SS but expresses a Pyrin-activating T6SS (Fig 3E) [15,30,31,32]. For B .…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

et al. 2016

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“…FMF is the most frequent monogenic autoinflammatory condition described so far. It differs from other inflammasomopathies in that it is inherited mostly in an autosomal recessive fashion, despite the fact that in FMF patients, systemic inflammation is caused by a gain of function in the pyrin protein causing aberrant activation of the pyrin inflammasome . It is not known why patients with only one allele mutated only rarely show signs of FMF.…”

Section: Non‐nlr Inflammasomesmentioning

confidence: 99%

“…It differs from other inflammasomopathies in that it is inherited mostly in an autosomal recessive fashion, despite the fact that in FMF patients, systemic inflammation is caused by a gain of function in the pyrin protein causing aberrant activation of the pyrin inflammasome. 39 Several musculoskeletal symptoms are present in FMF, including arthralgia and arthritis. Moreover, in individuals without apparent signs of FMF but harboring a heterozygous mutation in the MEFV gene, increased prevalence of seronegative rheumatoid arthritis was observed.…”

Section: Non -Nlr Infl Amma Some Smentioning

confidence: 99%

Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

117

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Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

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“…Inflammasome-dependent secretion of IL-1b and IL-18 is critical for immune control of many microbes [11][12][13][14][15][16] and may play an important role in vaccine adjuvant-induced responses [17]. However, dysregulation or inappropriate activation of inflammasomes can also produce severe autoinflammation [18][19][20][21] and contribute to autoimmune disorders [22][23][24], Alzheimer's disease [25], Parkinson's disease [26], and many other pathologic processes. To some extent, the roles of IL-1b and IL-18 overlap [27].…”

Section: Inflammasomes and Their Role In Diseasementioning

confidence: 99%

Bacterial secretion systems and regulation of inflammasome activation

Ratner

Orning

Lien

2016

Journal of Leukocyte Biology

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Innate immunity is critical for host defenses against pathogens, but many bacteria display complex ways of interacting with innate immune signaling, as they may both activate and evade certain pathways. Gram-negative bacteria can exhibit specialized nanomachine secretion systems for delivery of effector proteins into mammalian cells. Bacterial types III, IV, and VI secretion systems (T3SS, T4SS, and T6SS) are known for their impact on caspase-1-activating inflammasomes, necessary for producing bioactive inflammatory cytokines IL-1β and IL-18, key participants of anti-bacterial responses. Here, we discuss how these secretion systems can mediate triggering and inhibition of inflammasome signaling. We propose that a fine balance between secretion system-mediated activation and inhibition can determine net activation of inflammasome activity and control inflammation, clearance, or spread of the infection.

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The immunological function of familial Mediterranean fever disease protein Pyrin

Cited by 31 publications

References 57 publications

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

Inflammasomes contributing to inflammation in arthritis

Bacterial secretion systems and regulation of inflammasome activation

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