Fig 1.
Picornavirus genomic organization, life cycle, and relevant structures of the 5′-NCR.
(A) Schematic representation of picornavirus genome. Picornavirus positive single-strand RNA genome is composed of 2 NCRs in 5′ and 3′ flanking one open reading frame. The NCRs are highly structured and contain numerous functional RNA elements acting as regulators of the viral life cycle. The coding region encodes for a polyprotein that is co-translationally cleaved into 12–13 final viral proteins and 4 protein precursors by 3C viral proteinase. All picornaviruses share a common organization of the polyprotein into 3 regions: P1, P2, and P3 encoding for 4-3-4 viral proteins, respectively. P1 encodes for 4 structural proteins assembling the capsid, while P2 and P3 contain all nonstructural proteins. Some picornaviruses, including Cardioviruses and Aphthoviruses, also have an additional Leader (L) protein preceding the P1 region. Created with BioRender.com [1]. (B) Picornavirus life cycle. Binding to the cellular receptor triggers uncoating and release of the genomic RNA in the cytoplasm. Here, the IRES recruits the eukaryotic translational machinery to synthesize the polyprotein. The polyprotein is cleaved, leading to the production of single viral proteins. As viral proteins accumulate in the cytoplasm, the host functions are progressively hijacked to favor viral replication. Viral proteins interacting with cellular factors rearrange the membranes of internal organelles to form membranous vesicles, where the viral genome replication complex will be assembled. The RdRp, encoded by the 3D gene, replicates the positive-sense RNA genome into a negative-sense RNA, through a partially double-stranded RNA molecule known as RF. The negative-sense RNA genome is then used as a template for the synthesis by RdRp of many copies of the positive-sense RNA genomes in the RI that can either become the blueprint for more viral protein synthesis, serve as template for replication, or be incorporated in the nascent capsid. The viral capsid protein VP0, VP1, and VP3 auto-assemble into a protomer, assembly of the protomers into higher geometrical structures coordinates the formation of the final icosahedral capsid. After RNA encapsidation, the VP0 precursor self-cleaves into VP2 and VP4, allowing complete maturation of the virion. Viral particles egress occurs upon cell lysis. Created with BioRender.com [1]. (C) Schematic representation of the 5′-NCR of Cardioviruses EMCV and Mengovirus and Aphthovirus FMDV. The 3 species of picornavirus that have been described to carry a polyC tract share a similar organization of the 5′-NCR: The polyC tract is located between a hairpin structure named S-fragment and the type II IRES (domains I to V) and its flanked by pseudoknots. Created with BioRender.com. EMCV, Encephalomyocarditis virus; FMDV, foot-and-mouth disease virus; IFN, interferon; IRES, internal ribosome entry site; NCR, noncoding region; polyC, polycytidine; RdRp, RNA-dependent RNA polymerase; RF, replicative form; RI, replication intermediate.
Table 1.
Summary of polyC tract variants reported for Cardioviruses (EMCV and Mengovirus) and Aphthoviruses (FMDV) strains.
Fig 2.
Possible molecular mechanisms mediating the polyC function.
Detailed discussion of each potential molecular mechanism is included in the text. Created with BioRender.com. IFN, interferon; ITAF, IRES trans-acting factor; PABP, polyA-binding protein; PCBP, poly(rC)-binding protein; polyC, polycytidine; PTB, polypyrimidine tract–binding protein.