How does pUL21a target APC4 and APC5 for proteasome degradation? pUL21a does not contain a sequence domain that would suggest it as an E3 ligase, thus likely ruling out this possibility. Currently, we also do not know which subunit of the APC complex that pUL21a directly binds to so the precise mechanism that it uses to degrade APC4 and APC5 remains elusive. It is certainly possible that pUL21a may bind to a subunit neighboring to APC4 and APC5 so it can disrupt the APC structure leading to APC4 and APC5 degradation, or recruit a protein degradation enzyme (e.g. E3 ubiquitin ligase) to destabilize the subunits. However, knockdown of APC8 does not abrogate the ability of pUL21a to degrade APC4 and APC5, suggesting that APC8 is not involved and the presence of the entire complex is not required. Intriguingly, pUL21a itself is a highly unstable protein and likely degraded in a ubiquitin-independent manner [29, 40] . It is tempting to speculate that pUL21a may directly bind APC4 and APC5 and target them for degradation in a ubiquitin-independent manner. One focus of future work is to identify the APC component that pUL21a directly binds to and elucidate the mechanism of how pUL21a targets APC4 and APC5 to the proteasome.