Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation

Bo Zhang; Graziella Morace; Verena Gauss-Müller; Yuri Kusov

doi:10.1093/nar/gkm645

Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation

Bo Zhang, Graziella Morace, Verena Gauss-Müller^*, Yuri Kusov

^*Corresponding author for this work

Institute of Virology and Cell Biology

National Institute for Health

46 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Nucleic Acids Research
Volume	35
Issue number	17
Pages (from-to)	5975-5984
Number of pages	10
ISSN	0305-1048
DOIs	https://doi.org/10.1093/nar/gkm645
Publication status	Published - 09.2007

Funding

We thank Dr A. Andino, Dr M. Görlach, Dr G.J. Goodall, Dr M. Hentze, Dr M. Kiledjian, Dr R. Lloyd, Dr B. Moss, Dr R.E. Rhoads and Dr R. Zell for material used in this study. The help of Ms S. Cordes, M. Bohm, B. Andresen and K. Thiele-Bössel is highly appreciated. We are grateful to P.K. Müller for reading the manuscript. Work in the laboratory is funded by the Deutsche Forschungsgemeinschaft (DFG, projects Pe494/4 and Ga304/7-1). Funding to pay the Open Access publication charges for this article was provided by the DFG.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1093/nar/gkm645

Cite this

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title = "Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation",

abstract = "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 3Cpro). However, PABP is cleaved by HAV 3Cpro 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.",

author = "Bo Zhang and Graziella Morace and Verena Gauss-M{\"u}ller and Yuri Kusov",

year = "2007",

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doi = "10.1093/nar/gkm645",

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T1 - Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation

AU - Zhang, Bo

AU - Morace, Graziella

AU - Gauss-Müller, Verena

AU - Kusov, Yuri

PY - 2007/9

Y1 - 2007/9

N2 - 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 3Cpro). However, PABP is cleaved by HAV 3Cpro 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.

AB - 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 3Cpro). However, PABP is cleaved by HAV 3Cpro 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.

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DO - 10.1093/nar/gkm645

M3 - Journal articles

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SN - 0305-1048

VL - 35

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JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 17

ER -

Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation

Abstract

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The switch from translation to replication in the life cycle of the hepatitis A virus (HAV): A cell-virus interplay

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Poly(A) binding protein, C-terminally truncated by the hepatitis A virus proteinase 3C, inhibits viral translation

Abstract

Funding

Research Areas and Centers

Access to Document

Other files and links

Fingerprint

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The switch from translation to replication in the life cycle of the hepatitis A virus (HAV): A cell-virus interplay

Cite this