Deubiquitinase USP2a Sustains Interferons Antiviral Activity by Restricting Ubiquitination of Activated STAT1 in the Nucleus

• DOI: 10.1371/journal.ppat.1005764
• Publication Date: 2016-07-19T13:31:15Z
• Authors: Ying Ren; Peng Zhao; Jin Liu; Yukang Yuan; Qiao Cheng; Yibo Zuo; Liping Qian; Chang Liu; Tingting Guo; Liting Zhang; Xiaofang Wang; Guanghui Qian; Lemin Li; Jun Ge; Jianfeng Dai; Sidong Xiong; Hui Zheng
• Keywords: QH301-705.5; Immunoblotting; Real-Time Polymerase Chain Reaction; Transfection; Sendai virus; Cell Line; 12. Responsible consumption; 03 medical and health sciences; Endopeptidases; Humans; Immunoprecipitation; Biology (General); Cell Nucleus; 0303 health sciences; Ubiquitination; Vesiculovirus; RC581-607; Flow Cytometry; Protein Transport; STAT1 Transcription Factor; Microscopy, Fluorescence; Virus Diseases; Interferons; Immunologic diseases. Allergy; Ubiquitin Thiolesterase; Research Article; Signal Transduction

STAT1 is a critical transcription factor for regulating host antiviral defenses. STAT1 activation is largely dependent on phosphorylation at tyrosine 701 site of STAT1 (pY701-STAT1). Understanding how pY701-STAT1 is regulated by intracellular signaling remains a major challenge. Here we find that pY701-STAT1 is the major form of ubiquitinated-STAT1 induced by interferons (IFNs). While total STAT1 remains relatively stable during the early stages of IFNs signaling, pY701-STAT1 can be rapidly downregulated by the ubiquitin-proteasome system. Moreover, ubiquitinated pY701-STAT1 is located predominantly in the nucleus, and inhibiting nuclear import of pY701-STAT1 significantly blocks ubiquitination and downregulation of pY701-STAT1. Furthermore, we reveal that the deubiquitinase USP2a translocates into the nucleus and binds to pY701-STAT1, and inhibits K48-linked ubiquitination and degradation of pY701-STAT1. Importantly, USP2a sustains IFNs-induced pY701-STAT1 levels, and enhances all three classes of IFNs- mediated signaling and antiviral activity. To our knowledge, this is the first identified deubiquitinase that targets activated pY701-STAT1. These findings uncover a positive mechanism by which IFNs execute efficient antiviral signaling and function, and may provide potential targets for improving IFNs-based antiviral therapy.