USP12 translocation maintains interferon antiviral efficacy by inhibiting CBP acetyltransferase activity

Jin Liu; Lincong Jin; Xiangjie Chen; Yukang Yuan; Yibo Zuo; Ying Miao; Qian Feng; Hongguang Zhang; Fan Huang; Tingting Guo; Liting Zhang; Li Zhu; Feng Qian; Chuanwu Zhu; Hui Zheng

doi:10.1371/journal.ppat.1008215

USP12 translocation maintains interferon antiviral efficacy by inhibiting CBP acetyltransferase activity

PLoS Pathog. 2020 Jan 3;16(1):e1008215. doi: 10.1371/journal.ppat.1008215. eCollection 2020 Jan.

Authors

Jin Liu^{1

2

3}, Lincong Jin^{1

2}, Xiangjie Chen^{1

2}, Yukang Yuan^{1

2}, Yibo Zuo^{1

2}, Ying Miao^{1

2}, Qian Feng^{1

2}, Hongguang Zhang^{1

2}, Fan Huang^{1

2}, Tingting Guo^{1

2}, Liting Zhang^{1

2}, Li Zhu³, Feng Qian³, Chuanwu Zhu³, Hui Zheng^{1

2}

Affiliations

¹ International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
² Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China.
³ The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Antiviral Agents / metabolism
CREB-Binding Protein / antagonists & inhibitors*
CREB-Binding Protein / metabolism
Cytoplasm / metabolism
Enzyme Inhibitors / metabolism
HCT116 Cells
HEK293 Cells
HeLa Cells
Humans
Interferons / physiology*
Mice
Mice, Inbred C57BL
Protein Domains
RAW 264.7 Cells
STAT1 Transcription Factor / metabolism
Signal Transduction
Ubiquitin Thiolesterase / metabolism*

Substances

Antiviral Agents
Enzyme Inhibitors
STAT1 Transcription Factor
Stat1 protein, mouse
Interferons
CREB-Binding Protein
Crebbp protein, mouse
Ubiquitin Thiolesterase
Usp12 protein, mouse

Grants and funding

The study was funded by National Natural Science Foundation of China (31570865, 31770177 and 31970846), the National Key R&D Program of China (2018YFC1705500): 2018YFC1705505, the Key Project of University Natural Science Foundation of Jiangsu Province (18KJA180010), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Program of 1000 Young Talents, and Jiangsu Provincial Distinguished Young Scholars (BK20130004). HZ is the recipient of all above funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.