Oncotarget

Research Papers:

Insulin receptor substrate-4 interacts with ubiquitin-specific protease 18 to activate the Jak/STAT signaling pathway

Baihai Jiao, Xuezhen Shi, Yanzhao Chen, Haiyan Ye, Min Yao, Wenxu Hong, Shilin Li, Xiaoqiong Duan, Yujia Li, Yancui Wang and Limin Chen _

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Oncotarget. 2017; 8:105923-105935. https://doi.org/10.18632/oncotarget.22510

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Abstract

Baihai Jiao1, Xuezhen Shi1, Yanzhao Chen1, Haiyan Ye1, Min Yao1, Wenxu Hong2, Shilin Li1, Xiaoqiong Duan1, Yujia Li1, Yancui Wang1 and Limin Chen1,3

1Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Provincial Key Laboratory for Transfusion-Transmitted Infectious Diseases of Sichuan Province, Chengdu 610052, China

2Key Laboratory of Shenzhen for Histocompatibility and Immunogenetics, Shenzhen Blood Center, Shenzhen 518000, China

3Toronto General Research Institute, University Network and University of Toronto, Toronto M5G 1L6, Canada

Correspondence to:

Limin Chen, email: limin_chen_99@yahoo.com

Keywords: USP18; IRS4; Jak/STAT signaling pathway; HCV

Received: May 07, 2017    Accepted: November 03, 2017    Published: November 18, 2017

ABSTRACT

Ubiquitin-specific protease 18 (USP18) as a negative regulator of the Jak/STAT signaling pathway plays an important role in the host innate immune response. USP18 has been shown to bind to the type I interferon receptor subunit 2 (IFNAR2) to down-regulate the Jak/STAT signaling. In this study, we showed that insulin receptor substrate (IRS)-4 functioned as a novel USP18-binding protein. Co-precipitation assays revealed that two regions (amino acids 335–400 and 1094-1257) of IRS4 were related to bind to the C- terminal region of USP18. IRS4 binding to USP18 diminished the inhibitory effect of USP18 on Jak/STAT signaling. IRS4 over-expression enhanced while IRS4 knock-down suppressed the Jak/STAT signaling in the presence of IFN-a stimulation. As such, IRS4 increased IFN-a-mediated anti-HCV activity. Mechanistically, IRS4 promoted the IFN-a-induced Jak/STAT signaling by interact with USP18. These results suggested that IRS4 binds to USP18 to diminish the blunting effect of USP18 on IFN-a-induced Jak/STAT signaling. Our findings indicated that IRS4 is a novel USP18-binding protein that can be used to boost the host innate immunity to control HCV, and potentially other viruses that are sensitive to IFN-a.


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