Enhanced enteroviral infectivity via viral proteasemediated cleavage of Grb2-associated binder 1

Abstract

Coxsackievirus B3 (CVB3), an important human causative pathogen for viral myocarditis, pancreatitis, and meningitis, has evolved different strategies to manipulate the host signaling machinery to ensure successful viral infection.We previously revealeda crucial role for the ERK1/2 signaling pathway in regulating viral infectivity. However, the detail mechanism remains largely unknown. Grb2-associated binder 1 (GAB1) is an important docking protein responsible for intracellular signaling assembly and transduction. In this study, we demonstrated thatGAB1was proteolytically cleaved afterCVB3infection at G175 and G436 by virus-encoded protease 2Apro, independent of caspase activation. Knockdown of GAB1 resulted in a significant reduction of viral protein expression and virus titers. Moreover, we showed that virusinduced cleavage of GAB1 is beneficial to viral growth as theN-terminal proteolytic product ofGAB1 (GAB1-N1-174) further enhances ERK1/2 activation and promotes viral replication. Our results collectively suggest that CVB3 targets host GAB1 to generate a GAB1-N1-174 fragment that enhances viral infectivity, at least in part, via activation of the ERKpathway. The findings in this study suggest a novel mechanismthat CVB3 employs to subvert the host signaling and facilitate consequent viral replication.