MHC class I ubiquitination by a viral PHD/LAP finger protein

Abstract

The murine gamma-herpesvirus-68 K3 (MK3) is a PHD/LAP finger protein that downregulates major histocompatibility complex (MHC) class I expression. In transfected cell lines, MK3 was expressed in the endoplasmic reticulum (ER) membrane, where it bound the cytoplasmic tail of newly synthesized H-2D(b) glycoproteins and targeted them for degradation. Proteasome inhibitors blocked the degradation and led to an accumulation of ubiquitinated H-2D(b). Because this retained its native conformation, ubiquitination preceded any denaturation or dislocation to the cytosol. The PHD/LAP finger of MK3 was not required for H-2D(b) binding but was essential for its ubiquitination and degradation. Thus, gamma-herpesviruses have adapted the cellular PHD/LAP motif to immune evasion, apparently for the catalysis of MHC class I ubiquitination.