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

Abstract

// Baihai Jiao 1 , Xuezhen Shi 1 , Yanzhao Chen 1 , Haiyan Ye 1 , Min Yao 1 , Wenxu Hong 2 , Shilin Li 1 , Xiaoqiong Duan 1 , Yujia Li 1 , Yancui Wang 1 and Limin Chen 1, 3 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 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.