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Control of the innate immune response by the mevalonate pathway.

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Date
2016-08
Authors
Akula, Murali K
Shi, Man
Jiang, Zhaozhao
Foster, Celia E
Miao, David
Li, Annie S
Zhang, Xiaoman
Gavin, Ruth M
Forde, Sorcha D
Germain, Gail
Carpenter, Susan
Rosadini, Charles V
Gritsman, Kira
Chae, Jae Jin
Hampton, Randolph
Silverman, Neal
Gravallese, Ellen M
Kagan, Jonathan C
Fitzgerald, Katherine A
Kastner, Daniel L
Golenbock, Douglas T
Bergo, Martin O
Wang, Donghai
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(23 total)
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Abstract
Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.
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Journal article
Permalink
https://hdl.handle.net/10161/12409
Published Version (Please cite this version)
10.1038/ni.3487
Publication Info
Akula, Murali K; Shi, Man; Jiang, Zhaozhao; Foster, Celia E; Miao, David; Li, Annie S; ... Wang, Donghai (2016). Control of the innate immune response by the mevalonate pathway. Nat Immunol, 17(8). pp. 922-929. 10.1038/ni.3487. Retrieved from https://hdl.handle.net/10161/12409.
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Scholars@Duke

Wang

Donghai Wang

Assistant Professor in Medicine
Inflammation underlies a variety of human diseases such as obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, arthritis and cancer. Together, these diseases constitute a major challenge to the well being of modern human society. Understanding the fundamental mechanisms of inflammation may provide rationales for designing novel interventions to treat these maladies. Autoinflammatory diseases are an emerging family of illness, characterized by dysregulation of innate immune re
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