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

作者：Ren, Ying; Zhao, Peng; Liu, Jin; Yuan, Yukang; Cheng, Qiao; Zuo, Yibo; Qian, Liping; Liu, Chang; Guo, Tingting; Zhang, Liting; Wang, Xiaofang; Qian, Guanghui; li, Lemin; Ge, Jun; Dai, Jianfeng; Xiong, Sidong^*; Zheng, Hui^*

来源：PLoS Pathogens, 2016, 12(7): e1005764.

DOI：10.1371/journal.ppat.1005764

• PHOSPHORYLATION-ACETYLATION SWITCH
• IFN-GAMMA
• TYROSINE-PHOSPHATASE
• TRANSCRIPTION FACTOR
• GENE-EXPRESSION
• ALPHA RECEPTOR
• DEGRADATION
• LOCALIZATION
• BINDING
• METHYLATION

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.

• 出版日期2016-7
• 单位苏州大学; 河北医科大学