Dr. Hui Zheng’s group and Sidong Xiong’s group published an article entitled “Deubiquitinase USP2a Sustains Interferons Antiviral Activity by Restricting Ubiquitination of Activated STAT1 in the Nucleus” in PLoS Pathogens.
The interferon (IFNs) family of cytokines plays a critical role in the defense against viral infection and regulating innate immunity. Three classes of IFNs have been identified, all of which exert their activity by activating a signaling cascade comprised of Janus kinases (Jak) and signal transducers and activators of transcription (STAT). Amongst the seven members of the STAT family, STAT1 regulates all three classes of IFNs signaling. Activated STAT1 (pY701-STAT1) signaling largely determines the magnitude and duration of the IFNs signaling and antiviral efficacy.
In this article, the authors find that IFNs-induced pY701-STAT1 can be ubiquitinated remarkably, and pY701-STAT1 is the major form of ubiquitinated-STAT1 induced by IFNs signaling. Besides, unlike total STAT1 which stays very stable in cells, pY701-STAT1 can be rapidly downregulated by ubiquitin-proteasome system even if dephosphorylation of pY701-STAT1 is inhibited. Furthermore, the authors demonstrated that ubiquitinated pY701-STAT1 is located mostly in the nucleus, and inhibiting nuclear import of pY701-STAT1 significantly blocks ubiquitination and downregulation of pY701-STAT1, suggesting that pY701-STAT1 could be regulated by ubiquitin-proteasome system in the nucleus.
Furthermore, the authors identified the deubiquitinase USP2a as the important regulator of ubiquitinated pY701-STAT1 using the deubiquitinases-expressing library. USP2a translocated into the nucleus to bind to pY701-STAT1 and cleaved K48-linked ubiquitination of pY701-STAT1. Besides, USP
Ying Ren and Peng Zhao are the co-first authors of the paper. Contributing authors are Jin Liu, Yukang Yuan, Qiao Cheng, Yibo Zuo, Liping Qian and so on. Prof. Hui Zheng and Prof. Sidong Xiong are co-corresponding authors of the paper. This work has been supported by the grants from National Natural Science Foundation of China (31370873, 31570865), the Program of 1000 Young Talents, and Jiangsu Provincial Distinguished Young Scholars (BK20130004), the program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China (PCSIRT-IRT1075), the Jiangsu Provincial Innovative Research Team, and a project by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)