Chapter 24 : Picornavirus Proteinase-Mediated Shutoff of Host Cell Translation: Direct Cleavage of a Cellular Initiation Factor

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This chapter discusses the strategy used by picornaviruses belonging to the genera of enteroviruses, rhinoviruses, and aphthoviruses to interfere with host cell protein synthesis. First it describes the mechanism of initiation of capped mRNA and compares it with that of uncapped mRNA. It then discusses the role of the viral proteinases and their cellular targets. Finally it focuses on the effect of specific proteolytic cleavage and its function in the initiation of protein synthesis. There is ample evidence that 2A is the viral proteinase responsible for eIF4G cleavage, which results in the inactivation of cap-dependent translation leading to the shutoff of cellular protein synthesis. In addition, based on the known cleavage sites of 2A of HRV2 and 2A of coxsackievirus B4 in the viral polyprotein, sequence comparisons allowed the prediction of three potential cleavage sites in eIF4G. It has recently been demonstrated using an in vitro translation system that newly synthesized 2A of HRV2 is highly efficient in eIF4G cleavage. The discrepancy was particularly dramatic when viral replication was partially inhibited by guanidine-HCl, 3-methyl quercetin, monensin, or nigericin. In the presence of these inhibitors, eIF4G cleavage was found to be essentially complete, whereas cellular protein synthesis was only partially inhibited. Furthermore, generally the same initiation factors are involved in the translation of both types of mRNAs.

Citation: Kuechler E, Seipelt J, Liebig H, Sommergruber W. 2002. Picornavirus Proteinase-Mediated Shutoff of Host Cell Translation: Direct Cleavage of a Cellular Initiation Factor, p 301-311. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch24

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Hepatitis C virus
Foot-and-mouth disease virus
Viral Capsid Proteins
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Image of FIGURE 1

Effect of proteolytic cleavage of eIF4G by 2A and Lb: sequestration of the cap-binding domain of eIF4F from the ribosomal initiation complex. The two domains of the eIF4G structure are connected by the hinge region, which is the target of 2A and L. Cleavage by both enzymes sequesters the N-terminal domain comprising the binding sites for eIF4E (attached to the 5′-terminal mG cap structure) and for PABP ([poly(A) binding protein]. The C-terminal domain of eIF4G harboring the eIF4A- and eIF3-binding sites remains attached to the 40S ribosomal complex. Reprinted from reference 97 with permission from Elsevier Science.

Citation: Kuechler E, Seipelt J, Liebig H, Sommergruber W. 2002. Picornavirus Proteinase-Mediated Shutoff of Host Cell Translation: Direct Cleavage of a Cellular Initiation Factor, p 301-311. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch24
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Image of FIGURE 2

Comparison of 2A and of Lb cleavage sites in rabbit eIF4G with that of the respective viral polyproteins. Amino acid sequences at the eIF4GI cleavage sites of 2A and of Lb are indicated. 2A cleavage in the HRV2 polyprotein occurs between the C terminus of the capsid protein VP1 and the Ν terminus of 2A. L cleaves the FMDV polyprotein between the C terminus of L and the Ν terminus of the capsid protein VP4.

Citation: Kuechler E, Seipelt J, Liebig H, Sommergruber W. 2002. Picornavirus Proteinase-Mediated Shutoff of Host Cell Translation: Direct Cleavage of a Cellular Initiation Factor, p 301-311. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch24
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