Most core proteins are essential, and a majority can be found in herpesvirus virions composed of an icosahedral capsid of 162 capsomers, an amorphous tegument layer and a lipid bilayer membrane with embedded glycoproteins. Using the high-coverage core network, a map of conserved protein interactions in herpesviral particles was generated ( Figure 6A and S12). One outstanding example for a highly connected protein in this virion map is the mCMV M51 ortholog (HSV-1 UL33, VZV Orf25, EBV BFRF4 and KSHV Orf67.5), which interacted with 14 tegument proteins. Since (i) 11 of the 14 interactions (79%) of this protein were found in more than 1 species, (ii) most Y2H interactions were confirmed even under high concentrations of the competitive HIS3 inhibitor 3amino-1,2,4-triazole which can be used to suppress non-specific Y2H interactions ( Figure S13A and S13B), and (iii) a majority of interactions were confirmed by CoIP (Table S12) , we considered them as high-confidence interactions. Furthermore, 4 of the 5 interactions conserved in 4 herpesviral species are M51 interactions. One example is the interaction of mCMV M51 orthologs (HSV-1_UL33/VZV_25/EBV_BFRF4/KSHV_67.5) with M53 orthologs (HSV-1_UL31/VZV_27/EBV_BFLF2/KSHV_69), which also interact in 4 species with M50 orthologs (HSV-1_UL34/ VZV_24/EBV_BFRF1/KSHV_67). M50 and M53 and their orthologs are involved in the nuclear egress of viral capsids and are well-characterised in mCMV, HSV-1, EBV and pseudorabiesvirus [36, 37, 38, 39] . Both M50 in mCMV and its ortholog UL34 in HSV-1 recruit protein kinase C to the nuclear membrane, which subsequently phosphorylates lamins to dissolve the nuclear lamina allowing the capsids to reach the inner nuclear envelope [38, 40] . In mCMV, we confirmed 17/22 (.75%) (Table S12) of M51 interactions by CoIP, and showed that M51 is targeted to the nuclear membrane by M50 and co-localizes with both M50 and M53 ( Figure 6B ). Our results suggest that M51 and its orthologs are part of a larger protein complex and may be involved in nuclear egress. Since most of its interaction partners are present in the virion tegument we hypothesize that it plays a role in tegument formation, and represents a possible link between DNA packaging, nuclear egress and tegumentation.