EV71 3C protease induces apoptosis by cleavage of hnRNP A1 to promote apaf-1 translation.

Mei-Ling Li,Jing-Yi Lin,Jesse Davila Calderon,Gary Brewer,Bo-Shiun Chen,Shin-Ru Shih,Blanton S Tolbert,Kuo-Feng Weng,Eric Jan

doi:10.1371/journal.pone.0221048

Abstract

Enterovirus 71 (EV71) induces apoptosis to promote viral particle release. Earlier work showed that EV71 utilizes its 3C protease to induce apoptosis in a caspase-3-dependent pathway, though the mechanism is unknown. However, work from Vagner, Holcik and colleagues showed that host protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds the IRES of cellular apoptotic peptidase activating factor 1 (apaf-1) mRNA to repress its translation. In this work, we show that apaf-1 expression is essential for EV71-induced apoptosis. EV71 infection or ectopic expression of 3C protease cleaves hnRNP A1, which abolishes its binding to the apaf-1 IRES. This allows IRES-dependent synthesis of apaf-1, activation of caspase-3, and apoptosis. Thus, we reveal a novel mechanism that EV71 utilizes for virus release via a 3C protease–hnRNP A1–apaf-1–caspase-3–apoptosis axis.

Highlights

Enterovirus 71 (EV71) is a positive-stranded RNA virus in the genus Enterovirus, family Picornaviridae
To test whether EV71 infection cleaves and affects the abundance of Heterogeneous nuclear ribonucleoprotein (hnRNP) A1, SF268 cells were infected with EV71 and degradation of hnRNP A1 at various time points was determined by Western blot
We previously reported that 3Cpro activates caspase-3 to induce apoptosis in EV71-infected cells [11]

Summary

Introduction

Enterovirus 71 (EV71) is a positive-stranded RNA virus in the genus Enterovirus, family Picornaviridae. It is one of the major pathogens causing hand, foot and mouth disease (HFMD) in the Asia-Pacific region. Outbreaks of EV71 infection have occurred worldwide [5]. Apoptosis is a highly regulated, programmed cell death to eliminate damaged, aged, or virally infected cells. EV71 infection can induce apoptosis in various cell types through different mechanisms [6]. EV71 infection modulates the expression of miR-146a or miR-370 to induce apoptosis through targeting Son of sevenless homolog 1 (SOS1) and Growth arrest and DNA damage-inducible protein 45β (GADD45β) [7].

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