This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chevalier, M. S. Articles by Johnson, D. C. Search for Related Content PubMed PubMed Citation Articles by Chevalier, M. S. Articles by Johnson, D. C.

Human Cytomegalovirus US3 Chimeras Containing US2 Cytosolic Residues Acquire Major Histocompatibility Class I and II Protein Degradation Properties

Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 97239

Received 2 October 2002/ Accepted 17 January 2003

Human cytomegalovirus (HCMV) glycoprotein US2 increases the proteasome-mediated degradation of major histocompatibility complex (MHC) class I heavy chain (HC), class II DR- and DM- proteins, and HFE, a nonclassical MHC protein. US2-initiated degradation of MHC proteins apparently involves the recruitment of cellular proteins that participate in a process known as endoplasmic reticulum (ER)-associated degradation. ER-associated degradation is a normal process by which misfolded proteins are recognized and translocated into the cytoplasm for degradation by proteasomes. It has been demonstrated that truncated forms of US2, especially those lacking the cytoplasmic domain (CT), can bind MHC proteins but do not cause their degradation. To further assess how the US2 CT domain interacts with the cellular components of the ER-associated degradation pathway, we constructed chimeric proteins in which the US2 CT domain or the CT and transmembrane (TM) domains replaced those of the HCMV glycoprotein US3. US3 also binds both class I and II proteins but does not cause their degradation. Remarkably, chimeras containing the US2 CT domain caused the degradation of both MHC class I and II proteins although this degradation was less than that by wild-type US2. Therefore, the US2 CT and TM domains can confer on US3 the capacity to degrade MHC proteins. We also analyzed complexes containing MHC proteins and US2, US3, US11, or US3/US2 chimeras for the presence of cdc48/p97 ATPase, a protein that binds polyubiquitinated proteins and likely functions in the extraction of substrates from the ER membrane before the substrates meet proteasomes. p97 ATPase was present in immunoprecipitates containing US2, US11, and two chimeras that included the US2 CT domain, but not in US3 complexes. Therefore, it appears that the CT domain of US2 participates in recruiting p97 ATPase into ER-associated degradation complexes.

This article has been cited by other articles:

• Wiertz, E. J., Devlin, R., Collins, H. L., Ressing, M. E. (2007). Herpesvirus Interference with Major Histocompatibility Complex Class II-Restricted T-Cell Activation. J. Virol. 81: 4389-4396 [Full Text]  
• Hegde, N. R., Chevalier, M. S., Wisner, T. W., Denton, M. C., Shire, K., Frappier, L., Johnson, D. C. (2006). The Role of BiP in Endoplasmic Reticulum-associated Degradation of Major Histocompatibility Complex Class I Heavy Chain Induced by Cytomegalovirus Proteins. J. Biol. Chem. 281: 20910-20919 [Abstract] [Full Text]  
• Pande, N. T., Powers, C., Ahn, K., Fruh, K. (2005). Rhesus Cytomegalovirus Contains Functional Homologues of US2, US3, US6, and US11. J. Virol. 79: 5786-5798 [Abstract] [Full Text]  
• Wang, X., Connors, R., Harris, M. R., Hansen, T. H., Lybarger, L. (2005). Requirements for the Selective Degradation of Endoplasmic Reticulum-Resident Major Histocompatibility Complex Class I Proteins by the Viral Immune Evasion Molecule mK3. J. Virol. 79: 4099-4108 [Abstract] [Full Text]  
• Gnann, A., Riordan, J. R., Wolf, D. H. (2004). Cystic Fibrosis Transmembrane Conductance Regulator Degradation Depends on the Lectins Htm1p/EDEM and the Cdc48 Protein Complex in Yeast. Mol. Biol. Cell 15: 4125-4135 [Abstract] [Full Text]  
• Petersen, J. L., Morris, C. R., Solheim, J. C. (2003). Virus Evasion of MHC Class I Molecule Presentation. J. Immunol. 171: 4473-4478 [Full Text]  
• Hegde, N. R., Johnson, D. C. (2003). Human Cytomegalovirus US2 Causes Similar Effects on Both Major Histocompatibility Complex Class I and II Proteins in Epithelial and Glial Cells. J. Virol. 77: 9287-9294 [Abstract] [Full Text]