Viral ubiquitination and the destruction of MHC class I molecules. HHV-8 K3 and K5, and MHV-68 MK3, encode proteins with a RING finger–like PHD domain that recognizes MHC class I molecules via interactions between the transmembrane regions of the viral and the host molecule. The N-terminal PHD domain may recruit an E2 enzyme to stimulate ubiquitination, leading to proteasomal destruction in the case of MK3, or endocytosis and lysosomal destruction in the case of K3 and K5, respectively. HCMV US2 encodes an Ig-like transmembrane protein that binds to the MHC class I heavy chain in the ER. The short cytosolic tail of US2 is required to stimulate dislocation of heavy chains, perhaps by recruiting ubiquitinating enzymes. Ub, ubiquitin.