Chapter 16 : Processing Determinants and Functions of Cleavage Products of Picornavirus Polyproteins

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Picornaviruses employ a number of unique intracellular mechanisms and novel processes during their infectious cycles resulting in their being among the most successful of viral pathogens. This chapter begins with a discussion of the features of viral proteinases, continues with an outline of the functions of both precursor and mature viral polypeptides present during a picornaviral infection, and concludes with a brief summary of nonviral substrates cleaved by viral proteinases. Viral proteinases including L protein, 2A proteinase and 3C proteinase have been discussed in the chapter. The aphthoviruses and cardioviruses code for an L protein at the N terminus of their polyproteins. The cleavage activity of the L proteinase from foot-and-mouth disease virus (FMDV), an aphthovirus, has been well characterized. The 3C proteinase activity carries out the majority of the proteolytic processing of the viral polyprotein. The evolution of picornaviruses might dictate that the P1 to PN substrate positions be identical or similar to optimize polyprotein processing and maximize the generation of mature viral proteins. In vitro synthesized viral RNAs containing large inframe deletions within the P1 region are self-replicating in cultured cells, suggesting that the proteins required for viral RNA replication are located primarily within the P2 and P3 (nonstructural) regions of the genome. Since picornaviruses utilize a mechanism of translation that is cap independent, it is advantageous to the virus to inhibit nonessential cap-dependent cellular translation.

Citation: Leong L, Cornell C, Semler B. 2002. Processing Determinants and Functions of Cleavage Products of Picornavirus Polyproteins, p 187-197. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch16
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Image of FIGURE 1

Map of proteins encoded in picornavirus genomes. Shown is a schematic of a typical picornaviral genome. The 5′ end is covalently linked to the viral protein VPg (protein 3B), and the poly(A) tail at the 3′ end is genetically coded. The polyprotein is divided into structural (P1) and nonstructural products (P2 and P3). The vertical lines represent sites along the polyprotein that are cleaved by viral proteinases; however, there are precursor proteins (e.g., 2BC, 3AB, 3CD) that have functions distinct from their mature cleavage products. Only cardioviruses and aphthoviruses encode an L protein. The viral proteinase responsible for the majority of polyprotein processing is the 3C chymotrypsin-like proteinase, and precursor polypeptides contain 3C sequences (e.g., 3CD). In addition, enteroviruses and rhinoviruses utilize the 2A proteinase to carry out the primary cleavage event between the carboxy terminus of the P1 region and the amino terminus of 2A. Cardioviruses and aphthoviruses do not contain a proteolytically active form of 2A; however, this protein is self-cleaved from the amino terminus of 2B by an undefined mechanism. The L proteinase of aphthoviruses is a cysteine-type proteinase that cleaves between its carboxy terminus and the amino terminus of VP4. The L proteinase of cardioviruses is cleaved from the polyprotein at its amino terminus by 3C. Interestingly, aphthoviruses are unique in that they encode three tandemly repeated VPgs while all other picornavirus genomes contain only one VPg.

Citation: Leong L, Cornell C, Semler B. 2002. Processing Determinants and Functions of Cleavage Products of Picornavirus Polyproteins, p 187-197. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch16
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Image of FIGURE 2

Processing of P1 capsid proteins and assembly of virion particles. 3CD carries out the cleavage of the P1 capsid precursor in a reaction that requires the activity of a cellular cofactor. This results in the formation of VP0, VP3, and VP1, which assemble into a 5S protomer. Then, five protomers assemble to form the 14S protomer. Twelve 14S protomers then either assemble around an RNA molecule or form the 80S procapsid structure into which an RNA molecule is threaded. In either case, this assembly process results in the formation of a short-lived 150S provirion. Finally, this newly formed particle undergoes a maturation event (occurring by an undefined mechanism) resulting in the cleavage of VP0 into VP2 and VP4, resulting in the production of a mature virion.

Citation: Leong L, Cornell C, Semler B. 2002. Processing Determinants and Functions of Cleavage Products of Picornavirus Polyproteins, p 187-197. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch16
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Functions of picornavirus polypeptides

Citation: Leong L, Cornell C, Semler B. 2002. Processing Determinants and Functions of Cleavage Products of Picornavirus Polyproteins, p 187-197. In Semler B, Wimmer E (ed), Molecular Biology of Picornavirus. ASM Press, Washington, DC. doi: 10.1128/9781555817916.ch16

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