Control of the Innate Immune Response by the Mevalonate Pathway

Nat Immunol. 2016 Aug;17(8):922-9. doi: 10.1038/ni.3487. Epub 2016 Jun 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkyl and Aryl Transferases / genetics
  • Alkyl and Aryl Transferases / metabolism*
  • Animals
  • Cells, Cultured
  • Familial Mediterranean Fever / genetics
  • Familial Mediterranean Fever / metabolism*
  • Humans
  • Immunity, Innate
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Macrophages / physiology*
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Polyisoprenyl Phosphates / metabolism
  • Protein Processing, Post-Translational
  • Pyrin / genetics*
  • Signal Transduction
  • Toll-Like Receptors / metabolism

Substances

  • Inflammasomes
  • Interleukin-1beta
  • Polyisoprenyl Phosphates
  • Pyrin
  • Toll-Like Receptors
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • mevalonate kinase
  • geranylgeranyl pyrophosphate