DR5 is a restriction factor for human herpesviruses.

Restriction factors are dominant proteins that target different essential steps of the viral life cycle; thus, these proteins provide an early line of defense against viruses. Here, we found that the internalization of DR5, an important receptor of the extrinsic apoptotic pathway, initiates apoptosis to inhibit Kaposi sarcoma-associated herpesvirus (KSHV) lytic replication. An evolutionary analysis of the DR5 sequence demonstrated that three amino acids underwent positive selection in primates. Notably, one of these positive selection sites, A62, is essential for the antiviral function of DR5 and is important for the binding of DR5 to its ligand, TNF-related apoptosis-inducing ligand. Moreover, DR5 exhibits broad antiviral activity against and inhibits various herpesviruses, including Epstein-Barr virus, herpes simplex virus type 1, and herpes simplex virus type 2. As a countermeasure, the KSHV K5 protein interacts with DR5 and promotes DR5 degradation through the lysosomal and proteasomal degradation pathways; lysine 245 of DR5 is essential for K5-induced DR5 degradation. These findings demonstrate that DR5 is a restriction factor for human herpesviruses.