Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

Park, Yong Hwan; Remmers, Elaine F.; Lee, Wonyong; Ombrello, Amanda K.; Chung, Lawton K.; Zhao, Shilei; Stone, Deborah L.; Ivanov, Maya I.; Loeven, Nicole A.; Barron, Karyl S.; Hoffmann, Patrycja; Nehrebecky, Michele; Akkaya-Ulum, Yeliz Z.; Sağ, Erdal; Balcı-Peynircioğlu, Banu; Aksentijevich, Ivona; Gül, Ahmet; Rotimi, Charles N.; Chen, Hua; Bliska, James B.; Özen, Seza; Kastner, Daniel L.; Shriner, Daniel; Chae, Jae Jin

doi:10.1038/s41590-020-0705-6

Cited by 113 publications

(127 citation statements)

References 46 publications

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“…It has been hypothesized that FMF mutations were selected in the human population as a result of heterozygous advantage against Y. pestis infection during historic plague pandemics 5,16 . Recent population genetic data and experimental results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants are consistent with the idea that resistance to plague epidemics was a selective force for MEFV mutations in individuals of Mediterranean decent 19 …”

Section: Introductionmentioning

confidence: 74%

“…U937 cells, which do not natively express MEFV , were retrovirally transduced to ectopically overexpress wildtype pyrin or pyrin lacking the B30.2 domain. Following stimulation with LPS, there was more IL‐1β released from U937 cells expressing pyrin lacking the B30.2 domain as compared to wildtype, suggesting that the B30.2 domain negatively regulates pyrin in this system 19 …”

Section: Negative Regulation Of Pyrinmentioning

confidence: 98%

“…When truncated pyrin constructs were ectopically overproduced in HEK293T cells along with other inflammasome components, deletion of the B30.2 domain or replacement of the B30.2 with the TRIM5α B30.2 domain did not increase basal inflammasome activation, 9 indicating that pyrin is not negatively regulated by B30.2 domain in this overexpression system. More recently, Park et al 19 used human monocytic U937 cells to study the role of the B30.2 domain in regulating human pyrin. U937 cells, which do not natively express MEFV , were retrovirally transduced to ectopically overexpress wildtype pyrin or pyrin lacking the B30.2 domain.…”

Section: Negative Regulation Of Pyrinmentioning

confidence: 99%

“…Novel insights into the regulation and function of pyrin can be gained through the understanding of its interactions with toxins and effectors of bacterial pathogens 6 . This may be best exemplified by the interaction of pyrin with Yersinia effectors 16‐19 . Yersinia spp.…”

Section: Introductionmentioning

confidence: 99%

“…To counteract an effector‐triggered inflammasome response, Yersinia employ the effector YopM. YopM binds to pyrin, and hijacks host kinases to maintain inhibitory phosphorylation of the linker 16,17,19 . Inhibition of pyrin by YopM is essential for virulence in Y. pestis , the agent of plague 17 .…”

Section: Introductionmentioning

confidence: 99%

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The pyrin inflammasome and the Yersinia effector interaction

Malik

Bliska

2020

Immunological Reviews

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Pyrin is a cytosolic pattern‐recognition receptor that normally functions as a guard to trigger capase‐1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. The MEFV gene encoding human pyrin is preferentially expressed in phagocytes. Key domains in pyrin include a pyrin domain (PYD), a linker region, and a B30.2 domain. Binding of ASC to pyrin by a PYD‐PYD interaction triggers inflammasome assembly. Pyrin is held in an inactive conformation by negative regulation mechanisms to avoid premature inflammasome assembly. One mechanism of negative regulation involves phosphorylation of the linker by PRK kinase which in turn is positively regulated by active RhoA. The B30.2 domain also negatively regulates pyrin. Gain of function mutations in MEFV responsible for the autoinflammatory disease Familial Mediterranean Fever (FMF) map to exon 10 encoding the B30.2 domain. Insights into pyrin regulation have come from studies of several Yersinia effectors, which are injected into phagocytes and interact with the RhoA‐PRK‐pyrin axis during infection. Two effectors, YopE and YopT, inactivate RhoA to disrupt phagocytic signaling. To counteract an effector‐triggered immune response, a third effector, YopM, binds to and inhibits pyrin by hijacking PRK and RSK and directing linker phosphorylation. Inhibition of pyrin by YopM is required for virulence of Yersinia pestis, the agent of plague. Recent results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants show that gain of function MEFV mutations bypass inhibition by YopM. Population genetic data suggest that MEFV mutations were selected for in individuals of Mediterranean decent during historic plague pandemics. This review discusses current concepts of pyrin regulation and its interaction with Yersinia effectors.

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Section: Introductionmentioning

confidence: 74%

Section: Negative Regulation Of Pyrinmentioning

confidence: 98%

Section: Negative Regulation Of Pyrinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The pyrin inflammasome and the Yersinia effector interaction

Malik

Bliska

2020

Immunological Reviews

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Systemic Autoinflammatory Diseases

Peng,

Schnappauf,

De Jesus

et al. 2024

Manual of Molecular and Clinical Laboratory Immunology

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Inflammasome activation: from molecular mechanisms to autoinflammation

et al. 2022

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Inflammasomes are assembled by innate immune sensors that cells employ to detect a range of danger signals and respond with pro‐inflammatory signalling. Inflammasomes activate inflammatory caspases, which trigger a cascade of molecular events with the potential to compromise cellular integrity and release the IL‐1β and IL‐18 pro‐inflammatory cytokines. Several molecular mechanisms, working in concert, ensure that inflammasome activation is tightly regulated; these include NLRP3 post‐translational modifications, ubiquitination and phosphorylation, as well as single‐domain proteins that competitively bind to key inflammasome components, such as the CARD‐only proteins (COPs) and PYD‐only proteins (POPs). These diverse regulatory systems ensure that a suitable level of inflammation is initiated to counteract any cellular insult, while simultaneously preserving tissue architecture. When inflammasomes are aberrantly activated can drive excessive production of pro‐inflammatory cytokines and cell death, leading to tissue damage. In several autoinflammatory conditions, inflammasomes are aberrantly activated with subsequent development of clinical features that reflect the degree of underlying tissue and organ damage. Several of the resulting disease complications may be successfully controlled by anti‐inflammatory drugs and/or specific cytokine inhibitors, in addition to more recently developed small‐molecule inhibitors. In this review, we will explore the molecular processes underlying the activation of several inflammasomes and highlight their role during health and disease. We also describe the detrimental effects of these inflammasome complexes, in some pathological conditions, and review current therapeutic approaches as well as future prospective treatments.

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Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

Cited by 113 publications

References 46 publications

The pyrin inflammasome and the Yersinia effector interaction

The pyrin inflammasome and the Yersinia effector interaction

Systemic Autoinflammatory Diseases

Inflammasome activation: from molecular mechanisms to autoinflammation

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