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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Motifs
-
Amino Acid Sequence
-
Animals
-
Binding Sites
-
Cell Line
-
Cysteine Endopeptidases / physiology
-
Cysteine Proteinase Inhibitors / pharmacology
-
Down-Regulation
-
Endoplasmic Reticulum / metabolism
-
Gammaherpesvirinae / genetics
-
Gammaherpesvirinae / pathogenicity*
-
H-2 Antigens / chemistry
-
H-2 Antigens / metabolism*
-
Histocompatibility Antigen H-2D
-
Molecular Sequence Data
-
Multienzyme Complexes / antagonists & inhibitors
-
Multienzyme Complexes / physiology
-
Mutation
-
Proteasome Endopeptidase Complex
-
Protein Folding
-
Protein Structure, Tertiary
-
Transfection
-
Ubiquitin / metabolism*
-
Viral Proteins / chemistry
-
Viral Proteins / metabolism
-
Viral Proteins / pharmacology*
Substances
-
Cysteine Proteinase Inhibitors
-
H-2 Antigens
-
Histocompatibility Antigen H-2D
-
Multienzyme Complexes
-
Ubiquitin
-
Viral Proteins
-
Cysteine Endopeptidases
-
Proteasome Endopeptidase Complex