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

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 GSK3 alpha 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 GSK3 alpha and GSK3 beta, we found that GSK3 alpha but not GSK3 beta 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 GSK3 alpha phosphorylation at S21, thereby inactivating GSK3 alpha 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.