Autophagy triggered by p14.3.3z induces Akt full activation in intestinal epithelial cells.

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Akt activation has been associated with proliferation, differentiation and survival in epithelial cells. Phosphorylation of Thr308 of Akt by PDK1 is critical for optimal activation of its kinase activity. Despite the relevance of the phosphorylation of Akt at Threonine 308, the mechanism(s) regulating this process remain unclear. Here, we report that 14.3.3 proteins control Akt Thr308 phosphorylation during intestinal inflammation. Mechanistically we found that proinflammatory cytokines fully activate Akt by inducing degradation of the PDK1 inhibitor, 14.3.3η via autophagy. Interestingly we also observed that exposure of intestinal epithelial cells to proinflammatory cytokines reduces autophagy, suggesting that during inflammation full Akt activation is prevented. Notably, inhibition of 14.3.3 function by the chemical inhibitor BV02 results in uncontrolled Akt activation and increased cell death. Taken togetherour results show that 14.3.3 proteins tamper Akt activation to regulate its physiological functions, thereby providing a new mechanistic link between cell survival and apoptosis phenotype on intestinal epithelial cells during inflammation.