To confirm that decreased APC substrate accumulation during mutant virus infection was due to APC activity, we used shRNAs to knock down APC8 or the coactivator Cdh1 to deplete APC activity. Both APC8 and Cdh1 shRNAs efficiently reduced expression of their respective targets ( Figures 4D and S5B) . Importantly, APC8 knockdown restored geminin and Cdh1 levels in cells infected with ADpmUL21a PR-AA or ADsubUL21a virus to those with ADpmUL21a PH-AA or ADgfp virus. Likewise, Cdh1 knockdown restored geminin levels in cells infected with the pUL21a-deficient viruses. Thus, our results indicate that pUL21a association with the APC allows it to target APC4 and APC5 subunits for degradation to alter APC activity during infection.