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

PLoS Pathogens

Chang Liu¹  Ying Ren¹  Yukang Yuan¹  Tingting Guo¹  Xiaofang Wang¹  Yibo Zuo¹  Lemin Li¹  Qiao Cheng¹  Jin Liu¹  Jianfeng Dai¹  Liting Zhang¹  Jun Ge¹  Sidong Xiong¹  Peng Zhao¹  Guanghui Qian¹  Liping Qian¹  Hui Zheng² 

[1] Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China;Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Jiangsu, China

关键词: Ubiquitination;    293T cells;    Immunoprecipitation;    STAT signaling;    Immunoblotting;    Immune system proteins;    Vesicular stomatitis virus;    Interferons;   

DOI  :  10.1371/journal.ppat.1005764

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY