Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun, Di; Chen, Shun; Cheng, Anchun; Wang, Mingshu

Multiple viral proteins are generated through primary polyprotein processing and secondary polyprotein processing, and the analysis of polyprotein cleavage has shown that 3C pro is responsible for most of the cleavages among the 29 genera of the picornavirus family ( Figure 2 ). However, several exceptions have been found at the following four cleavage sites: L-VP4, VP4-VP2, P1-2A, and 2A-2B. In aphthovirus and erbovirus, the leader protein frees itself from VP0, whereas cardiovirus, kobuvirus, teschovirus, sapelovirus and senecavirus 3C pro s function in the primary cleavage [22, 23] . Moreover, 2A pro exhibits proteinase activity or translational recoding activity during primary cleavage. The junction between P1 and 2A is cleaved by proteolytic 2A pro in enteroviruses and potentially in sapelovirus type 2 (SV2) as well as PEV8. The separation of capsid proteins from replication proteins is mediated by ribosome skipping at the Asn-Pro-Gly-Pro site, inducing cleavage of 2A-2B in aphthoviruses, cardioviruses, teschoviruses, cosaviruses, sencaviruses and erboviruses [24] . Under other conditions, this cleavage is achieved by 3C pro [24, 25] . 3C pro presents in all picornaviruses, and is responsible for almost all secondary cleavages. For Aichi virus, in which L and 2A pro are not proteolytic, all cleavages are completed by only 3C pro and the 3CD precursor. A series of studies on enteroviruses and apthoviruses have revealed that cleavage at VP2-VP3 and VP3-VP1 can be accomplished more efficiently by 3CD pro than 3C pro [26] [27] [28] . [23, 28] . The release of mature and functional proteins from the polyprotein is dependent on primary and secondary cleavages and polyprotein processing differs slightly among diverse picornaviruses. In primary cleavage, L pro functions in apthoviruses by freeing itself (blue arrow), whereas the cleavage of P1-P2 is mediated by ribosome skipping in apthoviruses and cardioviruses (red triangle) [29] . The proteolytic 2A pro of enteroviruses is involved in primary cleavage and 3D pol cleavage to produce 3D' intermediate (red arrows). 3C pro and 3CD are responsible for a proportion of primary cleavages and almost all secondary cleavages (black arrow). The hepatovirus VP1-2A cleavage can be achieved by a host cell proteinase (green arrow). See the text for details.