Related Experiment Videos
MHC class I ubiquitination by a viral PHD/LAP finger protein
1Department of Pathology, Division of Virology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.
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.
Insights
Murine gamma-herpesvirus-68 K3 (MK3) protein targets major histocompatibility complex (MHC) class I for degradation. This viral protein hijacks a cellular motif to ubiquitinate MHC class I, aiding immune evasion.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Murine gamma-herpesvirus-68 K3 (MK3) is a viral protein.
- MK3 downregulates major histocompatibility complex (MHC) class I expression.
- MHC class I molecules are crucial for immune surveillance.
Purpose of the Study:
- To investigate the mechanism by which MK3 downregulates MHC class I.
- To determine the role of the PHD/LAP finger motif in MK3 function.
- To understand how gamma-herpesviruses utilize cellular machinery for immune evasion.
Main Methods:
- Transfected cell lines expressing MK3.
- Endoplasmic reticulum (ER) membrane localization studies.
- Analysis of H-2D(b) glycoprotein binding and degradation.
- Proteasome inhibitor treatment.
- Ubiquitination assays.
Main Results:
- MK3 localizes to the ER membrane and binds to newly synthesized H-2D(b) glycoproteins.
- MK3 targets H-2D(b) for proteasomal degradation.
- Degradation is preceded by ubiquitination, which occurs while H-2D(b) is in its native conformation.
- The PHD/LAP finger of MK3 is essential for H-2D(b) ubiquitination and subsequent degradation.
- Proteasome inhibition leads to accumulation of ubiquitinated H-2D(b).
Conclusions:
- Gamma-herpesviruses have adapted the cellular PHD/LAP motif for immune evasion.
- MK3 utilizes this motif to catalyze MHC class I ubiquitination, leading to its degradation.
- This mechanism allows the virus to evade host immune responses by reducing MHC class I surface expression.