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

PLoS One. 2019 Sep 9;14(9):e0221048. doi: 10.1371/journal.pone.0221048. eCollection 2019.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptotic Protease-Activating Factor 1 / genetics*
  • Apoptotic Protease-Activating Factor 1 / metabolism
  • Caspase 3 / genetics*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cysteine Endopeptidases / genetics*
  • Cysteine Endopeptidases / metabolism
  • Enterovirus A, Human / genetics*
  • Enterovirus A, Human / metabolism
  • Gene Expression Regulation
  • Heterogeneous Nuclear Ribonucleoprotein A1 / genetics*
  • Heterogeneous Nuclear Ribonucleoprotein A1 / metabolism
  • Host-Pathogen Interactions / genetics
  • Humans
  • Internal Ribosome Entry Sites
  • Muscle Cells / metabolism
  • Muscle Cells / virology
  • Neuroglia / metabolism
  • Neuroglia / virology
  • Protein Binding
  • Protein Biosynthesis*
  • Proteolysis
  • Signal Transduction
  • Vero Cells
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism

Substances

  • APAF1 protein, human
  • Apoptotic Protease-Activating Factor 1
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Internal Ribosome Entry Sites
  • Viral Proteins
  • hnRNPA1 protein, human
  • CASP3 protein, human
  • Caspase 3
  • Cysteine Endopeptidases
  • 3C proteases

Associated data

  • figshare/10.6084/m9.figshare.9728039