Inactivation of the Enzyme GSK3α by the Kinase IKKi Promotes AKT-mTOR Signaling Pathway that Mediates Interleukin-1-Induced Th17 Cell Maintenance

Muhammet F. Gulen, Katarzyna Bulek, Hui Xiao, Minjia Yu, Ji Gao, Lillian Sun, Eleonore Beurel, Oksana Kaidanovich-Beilin, Paul L. Fox, Paul E. DiCorleto, Jian an Wang, Jun Qin, David N. Wald, James R. Woodgett, Richard S. Jope, Julie Carman, Ashok Dongre, Xiaoxia Li

Research output: Contribution to journalArticle

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)800-812
Number of pages13
JournalImmunity
Volume37
Issue number5
DOIs
StatePublished - Nov 16 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Gulen, M. F., Bulek, K., Xiao, H., Yu, M., Gao, J., Sun, L., Beurel, E., Kaidanovich-Beilin, O., Fox, P. L., DiCorleto, P. E., Wang, J. A., Qin, J., Wald, D. N., Woodgett, J. R., Jope, R. S., Carman, J., Dongre, A., & Li, X. (2012). Inactivation of the Enzyme GSK3α by the Kinase IKKi Promotes AKT-mTOR Signaling Pathway that Mediates Interleukin-1-Induced Th17 Cell Maintenance. Immunity, 37(5), 800-812. https://doi.org/10.1016/j.immuni.2012.08.019