STING-mediated degradation of IFI16 negatively regulates apoptosis by inhibiting p53 phosphorylation at serine-392.

Interferon-γ–inducible factor 16 (IFI16) triggers stimulator of interferon (IFN) genes (STING)–dependent type I IFN production during host antiviral immunity and facilitates p53-dependent apoptosis during suppressing tumorigenesis. We have previously reported that STING-mediated IFI16 degradation negatively regulates type I IFN 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 immunoblot assays show that IFI16 and nutlin-3, a p53 pathway activator, synergistically induce apoptosis in U2OS and A549 cells. Protein kinase R–triggered phosphorylation of p53 at serine 392 is critical for the IFI16-p53–dependent apoptosis. However, overexpression of STING suppresses p53 serine 392 phosphorylation, p53 transcriptional activity, expression of p53 target genes, 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 cells, which suggests a protumorigenic role for STING in certain cancer types because of its potent ability to degrade upstream IFI16.