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Journal of Virology, August 2004, p. 8673-8686, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8673-8686.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Model for the Interaction of Gammaherpesvirus 68 RING-CH Finger Protein mK3 with Major Histocompatibility Complex Class I and the Peptide-Loading Complex

Xiaoli Wang,¹ Lonnie Lybarger,^1, Rose Connors,¹ Michael R. Harris,² and Ted H. Hansen^1*

Department of Pathology and Immunology,¹ Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110²

Received 17 February 2004/ Accepted 12 May 2004

The mK3 protein of gammaherpesvirus 68 and the kK5 protein of Kaposi's sarcoma-associated herpesvirus are members of a family of structurally related viral immune evasion molecules that all possess a RING-CH domain with ubiquitin ligase activity. These proteins modulate the expression of major histocompatibility complex class I molecules (mK3 and kK5) as well as other molecules like ICAM-1 and B7.2 (kK5). Previously, mK3 was shown to ubiquitinate nascent class I molecules, resulting in their rapid degradation, and this process was found to be dependent on TAP and tapasin, endoplasmic reticulum molecules involved in class I assembly. Here, we demonstrate that in murine cells, kK5 does not affect class I expression but does downregulate human B7.2 molecules in a TAP/tapasin-independent manner. These differences in substrate specificity and TAP/tapasin dependence between mK3 and kK5 permitted us, using chimeric molecules, to map the sites of mK3 interaction with TAP/tapasin and to determine the requirements for substrate recognition by mK3. Our findings indicate that mK3 interacts with TAP1 and -2 via their C-terminal domains and with class I molecules via their N-terminal domains. Furthermore, by orienting the RING-CH domain of mK3 appropriately with respect to class I, mK3 binding to TAP/tapasin, rather than the presence of unique sequences in class I, appears to be the primary determinant of substrate specificity.

Present address: Department of Cell Biology and Anatomy, Arizona Health Sciences Center, Tucson, AZ 85724.

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