Based on the results in the manuscript, in combination of our previous findings that CVB3 infection promotes host protein degradation, including cyclin D1, p53 and b-catenin, a model system on the role of the UPS in CVB3 replication is proposed in Fig. 6 . Coxsackievirus infection facilitates host protein polyubiquitination, which subsequently increases intracellular protein degradation by the proteasome and/or viral protein modification, such as 3D pol , by monoubiquitination. Degradation of host antiviral proteins provides a favorable environment for virus to achieve successful replication. Knockdown of ubiquitin decreases host protein degradation and viral protein ubiquitination. Proteasome inhibition blocks host protein degradation and viral protein ubiquitination by reducing recycled ubiquitin. DUB inhibitors further decreases the viral replication when used together with proteasome inhibitors through the additional reduction of recycled free ubiquitin.