Abstract
ABSTRACTViroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis. While many coronaviruses (CoVs) encode two viroporins, severe acute respiratory syndrome CoV (SARS-CoV) encodes three: proteins 3a, E, and 8a. Additionally, proteins 3a and E have a PDZ-binding motif (PBM), which can potentially bind over 400 cellular proteins which contain a PDZ domain, making them potentially important for the control of cell function. In the present work, a comparative study of the functional motifs included within the SARS-CoV viroporins was performed, mostly focusing on the roles of the IC and PBM of E and 3a proteins. Our results showed that the full-length E and 3a proteins were required for maximal SARS-CoV replication and virulence, whereas viroporin 8a had only a minor impact on these activities. A virus missing both the E and 3a proteins was not viable, whereas the presence of either protein with a functional PBM restored virus viability. E protein IC activity and the presence of its PBM were necessary for virulence in mice. In contrast, the presence or absence of the homologous motifs in protein 3a did not influence virus pathogenicity. Therefore, dominance of the IC and PBM of protein E over those of protein 3a was demonstrated in the induction of pathogenesis in mice.
Highlights
Viroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis
Viroporins constitute a large class of multifunctional viral proteins with ion channel (IC) activity that are widely distributed among different viral families [9]; highly pathogenic human viruses such as human immunodeficiency virus 1 (HIV-1), hepatitis C virus (HCV), influenza A virus (IAV), rotavirus (RV), enterovirus, and CoVs such as SARS-CoV and MERS-CoV encode them [10,11,12,13,14,15,16]
While the ΔE mutant showed 100-fold-lower titers, Δ3a titers decreased slightly (3-fold) (3 ϫ 107 PFU/ml). These results show that both proteins were required for optimal virus replication in cell culture
Summary
Viroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis. IMPORTANCE Collectively, these results demonstrate key roles for the ion channel and PBM domains in optimal virus replication and pathogenesis and suggest that the viral viroporins and PBMs are suitable targets for antiviral therapy and for mutation in attenuated SARS-CoV vaccines. Several viroporins have important roles in viral pathogenesis, promoting ion imbalances within cells [13, 19,20,21] or disrupting cellular pathways through protein-protein interactions [22] Given their potential as antiviral targets, there is substantial interest in the study of these proteins [18, 23]
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