Picornaviruses: A View from 3A

Abstract

Picornaviruses are comprised of a positive-sense RNA genome surrounded by a protein shell (or capsid). They are ubiquitous in vertebrates and cause a wide range of important human and animal diseases. The genome encodes a single large polyprotein that is processed to structural (capsid) and non-structural proteins. The non-structural proteins have key functions within the viral replication complex. Some, such as 3Dpol (the RNA dependent RNA polymerase) have conserved functions and participate directly in replicating the viral genome, whereas others, such as 3A, have accessory roles. The 3A proteins are highly divergent across the Picornaviridae and have specific roles both within and outside of the replication complex, which differ between the different genera. These roles include subverting host proteins to generate replication organelles and inhibition of cellular functions (such as protein secretion) to influence virus replication efficiency and the host response to infection. In addition, 3A proteins are associated with the determination of host range. However, recent observations have challenged some of the roles assigned to 3A and suggest that other viral proteins may carry them out. In this review, we revisit the roles of 3A in the picornavirus life cycle. The 3AB precursor and mature 3A have distinct functions during viral replication and, therefore, we have also included discussion of some of the roles assigned to 3AB.

Enterovirus D: A Small but Versatile Species

“…3A is also present as its uncleaved precursor 3AB. Interestingly, mature 3A and its precursor 3AB present distinct roles in EV replication [ 102 ]. For some EVs such as PV and CVB3 [ 70 , 103 ], 3A was described to inhibit protein trafficking, but this was not the case for other EVs such as EV-A71, RV-A2, and RV-B14 [ 99 , 102 , 104 ].…”

“…Interestingly, mature 3A and its precursor 3AB present distinct roles in EV replication [ 102 ]. For some EVs such as PV and CVB3 [ 70 , 103 ], 3A was described to inhibit protein trafficking, but this was not the case for other EVs such as EV-A71, RV-A2, and RV-B14 [ 99 , 102 , 104 ]. For PV and CVB3, this action is accomplished by hampering the function of GBF1 and ARF1 [ 104 , 105 , 106 ], two host proteins crucial for the assembly and budding of transport vesicles.…”

“…Concerning the 3A precursor 3AB, it was observed in the context of PV and EV-A71 infection that this protein exhibits nucleic acid chaperone activity, promoting strand annealing and the destabilisation of secondary structures [ 102 , 107 , 108 ]. 3AB together with 3CD interacts with both the 5′ CL and 3′ UTR of the positive RNA strand [ 102 , 109 ].…”

“…Concerning the 3A precursor 3AB, it was observed in the context of PV and EV-A71 infection that this protein exhibits nucleic acid chaperone activity, promoting strand annealing and the destabilisation of secondary structures [ 102 , 107 , 108 ]. 3AB together with 3CD interacts with both the 5′ CL and 3′ UTR of the positive RNA strand [ 102 , 109 ]. Actually, it has been reported that the full P3 precursor preferentially binds to the 5′ CL, which is subsequently cleaved, releasing 3AB and 3CD to start replication [ 102 , 110 ].…”

“…3AB together with 3CD interacts with both the 5′ CL and 3′ UTR of the positive RNA strand [ 102 , 109 ]. Actually, it has been reported that the full P3 precursor preferentially binds to the 5′ CL, which is subsequently cleaved, releasing 3AB and 3CD to start replication [ 102 , 110 ]. 3AB then promotes the RNA polymerase activity of 3D and stabilizes the complex between 3D, the VPg primer, and the RNA template [ 102 , 111 , 112 , 113 , 114 , 115 ].…”