Requirements for the selective degradation of endoplasmic reticulum-resident major histocompatibility complex class I proteins by the viral immune evasion molecule mK3.
Recent studies suggest that certain viral proteins co-opt endoplasmic reticulum (ER) degradation pathways to prevent the surface display of major histocompatibility complex class I molecules to the immune system. A novel example of such a molecule is the mK3 protein of gammaherpesvirus 68. mK3 belongs to an extensive family of structurally similar viral and cellular proteins that function as ubiquitin ligases using a conserved RING-CH domain. In the specific case of mK3, it selectively targets the rapid degradation of nascent class I heavy chains in the ER while they are associated with the class I peptide-loading complex (PLC). We present here evidence that the PLC imposes a relative proximity and/or orientation on the RING-CH domain of mK3 that is required for it to specifically target class I molecules for degradation. Furthermore, we demonstrate that full assembly of class I molecules with peptide is not a prerequisite for mK3-mediated degradation. Surprisingly, although the cytosolic tail of class I is required for rapid mK3-mediated degradation, we observed that a class I mutant lacking lysine residues in its cytosolic tail was ubiquitinated and degraded in the presence of mK3 in a manner indistinguishable from wild-type class I molecules. These findings are consistent with a "partial dislocation" model for turnover of ER proteins and define some common features of ER degradation pathways initiated by structurally distinct herpesvirus proteins.
Wang
Xiaoli
X
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Connors
Rose
R
Harris
Michael R
MR
Hansen
Ted H
TH
Lybarger
Lonnie
L
D000818:Animals; D017920:Antiporters / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018142:Gammaherpesvirinae / Q000276:immunology* / Q000472:pathogenicity*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D007136:Immunoglobulins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D017434:Protein Structure, Tertiary; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*
D017920:Antiporters; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D025801:Ubiquitin; D014764:Viral Proteins; C107762:tapasin; D044767:Ubiquitin-Protein Ligases