Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation.
Proteolytic cleavage of translation initiation factors is a means to interfere with mRNA circularization and to induce translation arrest during picornaviral replication or apoptosis. It was shown that the regulated cleavages of eukaryotic initiation factor (eIF) 4G and poly(A)-binding protein (PABP) by viral proteinases correlated with early and late arrest of host cap-dependent and viral internal ribosome entry site (IRES)-dependent translation, respectively. Here we show that in contrast to coxsackievirus, eIF4G is not a substrate of proteinase 3C of hepatitis A virus (HAV 3C(pro)). However, PABP is cleaved by HAV 3C(pro) in vitro and in vivo, separating the N-terminal RNA-binding domain (NTD) of PABP from the C-terminal protein-interaction domain. In vitro, NTD has a dominant negative effect on HAV IRES-dependent translation and an enhanced binding affinity to the RNA structural element pY1 in the 5' nontranslated region of the HAV RNA that is essential for viral genome replication. The results point to a regulatory role of PABP cleavage in RNA template switching of viral translation to RNA synthesis.
Zhang
Bo
B
Institute of Medical Molecular Biology, University of Lübeck, Germany.
Morace
Graziella
G
Gauss-Müller
Verena
V
Kusov
Yuri
Y
D000086042:3C Viral Proteases; D020121:5' Untranslated Regions / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D030041:Hepatitis A virus / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D010442:Peptide Chain Initiation, Translational; D039102:Poly(A)-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D014764:Viral Proteins / Q000378:metabolism*
D020121:5' Untranslated Regions; D039603:Eukaryotic Initiation Factor-4G; D039102:Poly(A)-Binding Proteins; D012367:RNA, Viral; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases