IFI16 Induction by Glucose Restriction in Human Fibroblasts Contributes to Autophagy through Activation of the ATM/AMPK/p53 Pathway

BACKGROUND Glucose restriction in cells increases the AMP/ATP ratio (energetic stress), which activates the AMPK/p53 pathway. Depending upon the energetic stress levels, cells undergo either autophagy or cell death. Given that the activated p53 induces the expression of IFI16 protein, we investigated the potential role of the IFI16 protein in glucose restriction-induced responses. METHODOLOGY/PRINCIPAL FINDINGS We found that glucose restriction or treatment of human diploid fibroblasts (HDFs) with the activators of the AMPK/p53 pathway induced the expression of IFI16 protein. The induced levels of IFI16 protein were associated with the induction of autophagy and reduced cell survival. Moreover, the increase in the IFI16 protein levels was dependent upon the expression of the functional ATM protein kinase. Importantly, the knockdown of the IFI16 expression in HDFs inhibited the activation of the ATM/AMPK/p53 pathway in response to glucose restriction and also increased the survival of HDFs. CONCLUSIONS/SIGNIFICANCE Our observations demonstrate a role for the IFI16 protein in the energetic stress-induced regulation of autophagy and cell survival. Additionally, our findings also indicate that the loss of IFI16 expression, as found in certain cancers, may provide a survival advantage to cancer cells in microenvironments with low glucose levels.