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; Limin Chen

doi:10.18632/oncotarget.22510

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

Oncotarget. 2017 Nov 18;8(62):105923-105935. doi: 10.18632/oncotarget.22510. eCollection 2017 Dec 1.

Authors

Baihai Jiao¹, Xuezhen Shi¹, Yanzhao Chen¹, Haiyan Ye¹, Min Yao¹, Wenxu Hong², Shilin Li¹, Xiaoqiong Duan¹, Yujia Li¹, Yancui Wang¹, Limin Chen^{1

3}

Affiliations

¹ Institute 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.
² Key Laboratory of Shenzhen for Histocompatibility and Immunogenetics, Shenzhen Blood Center, Shenzhen 518000, China.
³ Toronto General Research Institute, University Network and University of Toronto, Toronto M5G 1L6, Canada.

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.

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