USP12 translocation maintains interferon antiviral efficacy by inhibiting CBP acetyltransferase activity

Abstract

CREB-binding protein (CBP) participates in numerous transcription events. However, cellintrinsic 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.

A Hepatitis B Virus-Derived Peptide Exerts an Anticancer Effect via TNF/iNOS-producing Dendritic Cells in Tumor-Bearing Mouse Model

“…First, we found that Poly6 treatment, capable of exerting anti-HIV-1 effects, leads to IFN-I production in DCs, the DC2.4 cell line, and BMDCs via mitochondrial stress-mediated cytosolic exposure of mitochondrial DNA ( Figure 1 B and Figure S1C–E ). Increasing evidence has shown that various drugs targeting molecules that modulate host acetylation status, such as histone acetylation transferases (HATs) or histone deacetylases (HDACs), affect mitochondrial homeostasis or metabolism [ 19 , 35 , 36 ] or enhance IFN-I production via acetylation modification of phosphorylated-signal transducer and activator of transcription 1 (p-STAT-1) [ 37 ] or IFN regulatory factor 3 (IRF-3) [ 38 ]. However, the links between cellular modulation and induced IFN-I production found in Poly6-treated DCs require further elucidation in future studies.…”

An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities

“…Additionally, USP12 positively regulates IFN antiviral signaling independently of its deubiquitinase activity. Upon IFN treatment, USP12 accumulates in the nucleus, blocks the CREB-binding protein-induced acetylation of p-STAT1, and thus inhibits the dephosphorylation effects of TCPTP on p-STAT1, which ultimately maintains the nuclear p-STAT1 levels and IFN antiviral efficacy ( 114 ).…”

<p>Targeting IFN/STAT1 Pathway as a Promising Strategy to Overcome Radioresistance</p>

“…53 Liu and colleagues demonstrate that Type 1 IFN signaling stimulates the translocation of USP12 from cytoplasm to the nucleus, that blocks the acetylation effect of CREB-binding protein (CBP) in nucleus. 54 Therefore, in radioresistant cancer cells, aberrant IFNs signaling reduces the acetylation of STAT1 and inhibits the dephosphorylation of STAT1, leading to the high expression of STAT1. 53,54 Consequently, balance between dynamic phosphorylation and acetylation of IFN-dependent STAT1 signaling regulates cancer response to RT.…”

“…54 Therefore, in radioresistant cancer cells, aberrant IFNs signaling reduces the acetylation of STAT1 and inhibits the dephosphorylation of STAT1, leading to the high expression of STAT1. 53,54 Consequently, balance between dynamic phosphorylation and acetylation of IFN-dependent STAT1 signaling regulates cancer response to RT. The interactions of STAT1 and ISGs' roles in radiation-induced cell death are still unknown in various cancers.…”