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Göteborgs universitets publikationer

Control of the innate immune response by the mevalonate pathway

Författare och institution:
Murali K Akula (Institutionen för medicin, avdelningen för molekylär och klinisk medicin & Sahlgrenska Cancer Center); M. Shi (-); Z. Z. Jiang (-); C. E. Foster (-); D. Miao (-); A. S. Li (-); X. M. Zhang (-); R. M. Gavin (-); S. D. Forde (-); G. Germain (-); S. Carpenter (-); C. V. Rosadini (-); K. Gritsman (-); J. J. Chae (-); R. Hampton (-); N. Silverman (-); E. M. Gravallese (-); J. C. Kagan (-); K. A. Fitzgerald (-); D. L. Kastner (-); D. T. Golenbock (-); M. O. Bergo (-); D. H. Wang (-)
Publicerad i:
Nature Immunology, 17 ( 8 ) s. 922-+
ISSN:
1529-2908
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2016
Språk:
engelska
Fulltextlänk:
Sammanfattning (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 p110 delta. Macrophages that were deficient in GGTase I or p110 delta exhibited constitutive release of interleukin 1 beta 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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Klinisk medicin
Nyckelord:
phosphoinositide 3-kinase, protein prenylation, kinase-deficiency, cancer-therapy, ras, activation, cells, lipopolysaccharide, inflammasome, phosphorylation, Immunology
Postens nummer:
241576
Posten skapad:
2016-09-09 13:45

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