Finally, to determine if conserved intra-viral interactions allow viral proteins to interact across different species, we tested four interactions which were detected in at least two herpesviruses in the original screens by Y2H and LUMIER (luminescence-based mammalian interactome mapping) pull-down assays ( Figure S10A and B) [34] . While Y2H in general yielded few cross-species interactions, we detected a larger number of interactions by LUMIER ( Figure S10B ). The cross-species interactions between the HSV-1 UL11 and UL16 tegument and between the HSV-1 UL19 and UL35 capsid orthologs were mainly observed within a specific subfamily, in accordance with previous observations by Schnee et al. [35] . For the two other interactions, involving orthologs with both a high and low degree of sequence similarity based on Table S6 , we saw a more promiscuous interaction pattern. HSV1 UL14 for example was able to interact with HSV-1 UL33 and its orthologs in all five species, suggesting that sequence similarity might be a poor predictor of interspecies interactions in herpesviruses. Additionally, we tested 4 core and 4 noncore VZV baits against prey libraries of all five viruses. As expected, the intraspecies analysis (VZV baits against VZV preys) yielded the highest fraction of positive interactions (2.8%), compared to 0.5% positive interactions in the cross-species screens. Of the positive crossspecies interactions we observed 4 core-core, 15 core-noncore and 2 noncore-noncore interactions (Table S11 ). When the number of positive interactions was correlated to the number of interactions tested for each class, we observed a significant enrichment of positive interactions for the core-core and core-noncore classes compared to the noncore-noncore class ( Figure S11 ).