Viral security proteins: counteracting host defences

Abstract

Interactions with host defences are key aspects of viral infection. Various viral proteins perform counter-defensive functions, but a distinct class, called security proteins, is dedicated specifically to counteracting host defences. Here, the properties of the picornavirus security proteins L and 2A are discussed. These proteins have well-defined positions in the viral polyprotein, flanking the capsid precursor, but they are structurally and biochemically unrelated. Here, we consider the impact of these two proteins, as well as that of a third security protein, L(*), on viral reproduction, pathogenicity and evolution. The concept of security proteins could serve as a paradigm for the dedicated counter-defensive proteins of other viruses.

Figure 1. Leader and 2A proteins of picornaviruses.

The organization of an 'idealized' picornaviral polyprotein is shown, with specific viral leader (L) and 2A proteins given below; protein sizes are not to scale but give approximate relative lengths. There is great variability in L and 2A proteins. Multiple L and 2A proteins are known for some viral genera. Several picornaviruses do not possess L but have large 2A proteins. Cosaviruses contain no L and only a very short 2A. Other viruses (for example, some sapeloviruses) possess an unusually long L (we propose that in this case it might correspond to at least two separate polypeptides; see Supplementary information S1 (figure)) and a very short 2A (if there is a 2A peptide at all). Remarkably, other sapeloviruses possess a long 2A and a short L. Notable differences in the organization of the L and 2A proteins can occur among representatives of the same genus, such as in cardioviruses and parechoviruses. Well-defined amino acid motifs are indicated. See main text for details about the H-NC and AIG1 domains. L^*, alternative leader protein encoded by an alternative reading frame beginning in the L-encoding sequence; P↓, the NPG(P) motif, which interrupts translation at the proline residue; Pro, protease; VPg, primer for RNA synthesis; Zn, zinc finger.

Figure 2. Relationships between the presence of distinct security proteins and other evolutionary hallmarks of picornaviruses.

The distribution of security proteins among different viruses is not congruent with either the type of internal ribosome entry site (IRES; the key cis-acting element responsible for cap-independent translation of picornavirus RNAs) or the topology of the RNA-dependent RNA polymerase (RdRP) tree. For example, viruses harbouring type II IRESs can possess different L proteins (aphthoviruses and cardioviruses) or be devoid of this protein (cosaviruses). A similar situation occurs with viruses that use type IV IRESs. Conversely, different kobuviruses can possess unrelated IRESs. 2A proteins with the H-NC motif are present in viruses of distant RdRP lineages (kobuviruses on the one hand and avihepatoviruses, parechoviruses and tremoviruses on the other), but this motif is not shared by more closely related viruses (for example, it is present in tremoviruses but absent in hepatoviruses). The same pattern is characteristic of the 2A proteins that contain the NPG(P) motif (which interrupts translation at the indicated proline residue; shown by P↓). The closely related seal picornavirus type 1 (SePV-1), duck hepatitis A virus (DHV), Ljungan virus (LV) and human parechovirus type 2 (HPeV-2) each harbour a distinct 2A protein. Well-defined amino acid motifs are indicated. Viral RdRP protein sequences were taken from GenBank. Multiple alignments of protein sequences were constructed using CLUSTAL-X2. The RdRP tree was constructed by using MrBayes with default parameters. Solenopsis invicta virus 2 (SolV-2) was used as the outgroup. AEV, avian encephalomyelitis virus; AiV, Aichi virus; ASV, avian sapelovirus; EMCV, encephalomyocarditis virus; ERBV, equine rhinitis B virus; FMDV, foot-and-mouth disease virus; HAV, hepatitis A virus; HCoSV-A, human cosavirus A; HPV-1, human poliovirus type 1 str. Mahoney; HRV, human rhinovirus A101; PKV, porcine kobuvirus; Pro, protease; PSV, porcine sapelovirus; PTV, porcine teschovirus; SalV, Salivirus NG-J1; SSV, simian sapelovirus; SVV, Seneca Valley virus; TMEV, Theiler's murine encephalomyelitis virus; Zn, zinc finger.

Figure 3. Major biological functions of the best studied but unrelated security proteins.

There is a striking similarity between the functional activities of the enterovirus 2A protease (2A^pro) and the cardiovirus leader protein (L), but the underlying mechanisms by which these functions are carried out are fundamentally different. By contrast, the known functional activities of aphthovirus L, which is a protease (L^pro), seem to be more limited. IRF3, interferon regulatory factor 3; NF-κB, nuclear factor-κB.