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Journal of Virology, April 2005, p. 4099-4108, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4099-4108.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Requirements for the Selective Degradation of Endoplasmic Reticulum-Resident Major Histocompatibility Complex Class I Proteins by the Viral Immune Evasion Molecule mK3

Department of Pathology and Immunology, Washington University School of Medicine,¹ Department of Pediatrics, St. Louis Children's Hospital, St. Louis, Missouri,² Department of Cell Biology and Anatomy, University of Arizona Health Sciences Center, Tucson, Arizona³

Received 27 July 2004/ Accepted 23 October 2004

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.

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