HCMV has been shown to have two different means to regulate the anaphase-promoting complex (APC) during infection [24, 27, 28] . It can induce phosphorylation of APC co-activator Cdh1, and it induces dissociation of the complex by promoting proteasomal degradation of two components of the bridge subcomplex, APC4 and APC5. The viral protein pUL97 appears to be responsible for Cdh1 phosphorylation [24] . However, pUL97 is an HCMV-encoded kinase that has many reported roles [26, 35] . How this particular pUL97 activity impacts HCMV infection remains elusive. Importantly, the viral factor or precise molecular mechanism mediating APC4 and APC5 degradation has not been identified, and how APC disruption contributes to HCMV replication is not known. Here, we have identified the HCMV protein pUL21a as the viral factor that mediates APC disruption. It does so by interacting with the APC and inducing proteasome-dependent degradation of APC4 and APC5, which results in complex dissociation. This is the first identified viral protein that modulates the APC in this manner. We also show, for the first time, the impact of viral modulation of the APC, particularly by pUL21a, on HCMV replication. Loss of pUL21amediated APC regulation has minimal impact on virus replication but the combined loss of both pUL97-and pUL21a-mediated regulation markedly attenuates growth of the virus relative to single loss of pUL21a-or pUL97-mediated regulation. Our studies support a working model in which HCMV uses pUL97mediated Cdh1 phosphorylation and pUL21a-mediated complex disruption to control APC activity for efficient virus infection (Figure 7 ). Why has HCMV developed these two distinct mechanisms that seemingly lead to a similar biological consequence? It is possible that these two mechanisms have differential roles in HCMV infection under different conditions or in particular cell types, even though either one seems sufficient and can compensate for loss of the other in fibroblasts. Alternatively, it is possible that these two mechanisms serve as the fallback for one another or act synergistically to maximize the ability of the virus to acquire a complete control of the APC during infection. In any event, the fact that HCMV uses multiple means to subvert the APC underlines its critical role in HCMV infection. This is particularly true for large DNA viruses such as HCMV, which often encode multiple viral factors to regulate the same or related cellular targets central to their infection [36] . However, it is often challenging to dissect these intertwined viral mechanisms during infection because of the presence of other factors targeting the same process. The regulation of the APC represents one such critical but complex viral regulatory strategy, and our studies shed light into its role and mechanism during HCMV infection.