USP12 translocation maintains interferon antiviral efficacy by inhibiting CBP acetyltransferase activity

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Abstract
CREB-binding protein (CBP) participates in numerous transcription events. However, cell-intrinsic inhibitors of CBP are poorly defined. Here, we found that cellular USP12 interacts with the HAT domain of CBP and inhibits CBP’s acetyltransferase activity. Interestingly, USP12 positively regulates interferon (IFN) antiviral signaling independently of its deubiquitinase activity. Furthermore, we found that in IFN signaling USP12 translocates from the cytoplasm to the nucleus. The decrease in cytoplasmic USP12 facilitates CBP-induced acetylation and activation of IFN signaling proteins in the cytoplasm. Moreover, USP12 accumulation in the nucleus blocks CBP-induced acetylation of phosphorylated STAT1 (p-STAT1) and therefore inhibits the dephosphorylation effects of TCPTP on p-STAT1, which finally maintains nuclear p-STAT1 levels and IFN antiviral efficacy. USP12 nuclear translocation extends our understanding of the regulation of the strength of IFN antiviral signaling. Our study uncovers a cell-intrinsic regulation of CBP acetyltransferase activity and may provide potential strategies for IFN-based antiviral therapy. Activated p-STAT1 is a determinant for the strength of IFN antiviral signaling. We and other groups have demonstrated that activated p-STAT1 is regulated by multiple protein post-translational modifications, including phosphorylation, acetylation and ubiquitination. In this study, we revealed that CBP-mediated acetylation regulation of p-STAT1 is modulated by the deubiquitinase USP12 in a deubiquitinase activity-independent manner. USP12 translocates into the nucleus in IFN signaling, which critically regulates nuclear p-STAT1 levels and IFN antiviral activity by inhibiting CBP’s acetyltransferase activity. Importantly, we demonstrated that USP12 is a cell-intrinsic inhibitor of the acetyltransferase CBP. These findings promote the understanding of delicate regulation of both CBP-mediated acetylation and IFN antiviral signaling.

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