Inactivation of the enzyme GSK3α by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance

Immunity. 2012 Nov 16;37(5):800-12. doi: 10.1016/j.immuni.2012.08.019. Epub 2012 Nov 8.

Abstract

Interleukin-1 (IL-1)-induced activation of the mTOR kinase pathway has major influences on Th17 cell survival, proliferation, and effector function. Via biochemical and genetic approaches, the kinases IKKi and GSK3α were identified as the critical intermediate signaling components for IL-1-induced AKT activation, which in turn activated mTOR. Although insulin-induced AKT activation is known to phosphorylate and inactivate GSK3α and GSK3β, we found that GSK3α but not GSK3β formed a constitutive complex to phosphorylate and suppress AKT activation, showing that a reverse action from GSK to AKT can take place. Upon IL-1 stimulation, IKKi was activated to mediate GSK3α phosphorylation at S21, thereby inactivating GSK3α to promote IL-1-induced AKT-mTOR activation. Thus, IKKi has a critical role in Th17 cell maintenance and/or proliferation through the GSK-AKT-mTOR pathway, implicating the potential of IKKi as a therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Growth Processes / physiology
  • Enzyme Activation
  • Glycogen Synthase Kinase 3 / immunology
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • I-kappa B Kinase / metabolism*
  • Insulin / immunology
  • Insulin / metabolism
  • Interleukin-1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Serine-Threonine Kinases / immunology
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / immunology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / immunology
  • TOR Serine-Threonine Kinases / metabolism*
  • Th17 Cells / cytology
  • Th17 Cells / enzymology
  • Th17 Cells / immunology
  • Th17 Cells / metabolism*

Substances

  • Insulin
  • Interleukin-1
  • mTOR protein, mouse
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • I-kappa B Kinase
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha