Antiviral properties of BST-2 and Kaposi's sarcoma-associated herpesvirus countermeasures

Kaposi’s sarcoma–associated herpesvirus (KSHV) uses immune‑evasion strategies to support successful infection, including the activity of its viral E3 ubiquitin ligase, K5. While K5 is known to downregulate MHC class I, this study shows that it also targets the antiviral factor BST‑2, which restricts release of enveloped viruses by tethering virions to the cell surface. We demonstrate that K5 ubiquitinates lysines on the cytoplasmic tail of BST‑2 after it exits the ER, directing it to lysosomal degradation. In the absence of K5, BST‑2 restricts KSHV egress. These findings identify BST‑2 as a bona fide K5 substrate and highlight K5’s role in countering innate antiviral defenses.