J Biol Chem. 2021 Jun 30:100930. doi: 10.1016/j.jbc.2021.100930. Online ahead of print.
Interferon-γ-inducible factor 16 (IFI16) triggers stimulator of interferon genes (STING)-dependent type I interferon (IFN-I) production during host antiviral immunity and facilitates p53-dependent apoptosis during suppressing tumorigenesis. We have previously reported that STING-mediated IFI16 degradation negatively regulates IFN-I production. However, it is unknown whether STING also suppresses IFI16/p53-dependent apoptosis via degradation of IFI16. Here, our results from flow cytometry apoptosis detection and immunoblots assays show that IFI16 and Nutlin-3, a p53 pathway activator, synergistically induce apoptosis in U2OS and A549 cells. Protein kinase R (PKR)-triggered phosphorylation of p53 at serine-392 (Ser392) is critical for the IFI16-p53-dependent apoptosis. However, overexpression of STING suppressed p53 Ser392 phosphorylation, p53 transcriptional activity, p53-target gene expression, and p53-dependent mitochondrial depolarization and apoptosis. In summary, our current study demonstrates that STING-mediated IFI16 degradation negatively regulates IFI16 mediated p53-dependent apoptosis in osteosarcoma and non-small cell lung cancer (NSCLC) cells, which suggests a pro-tumorigenic role for STING in certain cancer types due to its potent ability to degrade upstream IFI16.