To uncover the underlying mechanisms of the antiviral activities of proteasome inhibitors, we chose to use the well-characterized HeLa cells to further our study. We first examined the role of proteasome inhibition in CVB3 replication. As shown in Fig. 1 , we found that proteasome inhibitor, MG132, significantly reduced CVB3 viral RNA synthesis (Fig. 1A) . Both proteasome inhibitors used in the study, MG132 and lactacystin, decreased the synthesis of CVB3 capsid protein, VP1, in a dose-dependent manner (Fig. 1B ). In addition, two inhibitors inhibited CVB3 viral titers by up to fifteen folds (Fig. 1C) . Although MG132 and lactacystin significantly inhibited cellular 20S proteasome activities, we have previously demonstrated there was no apparent difference in proteasome activities between CVB3-infected and sham-infected HeLa cells [9] . Together, these results suggest that efficient replication of CVB3 requires the intact UPS function rather than the core proteasome activity alone.