Control of the innate immune response by the mevalonate pathway.
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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https://hdl.handle.net/10161/12409Published Version (Please cite this version)
10.1038/ni.3487Publication 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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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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