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J. Biol. Chem., Vol. 281, Issue 40, 30063-30071, October 6, 2006

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Ubiquitination of MHC Class I Heavy Chains Is Essential for Dislocation by Human Cytomegalovirus-encoded US2 but Not US11^*

From the Department of Medical Microbiology, Leiden University Medical Center, Box 9600, 2300 RC Leiden, The Netherlands

The human cytomegalovirus-encoded glycoproteins US2 and US11 target newly synthesized major histocompatibility complex class I heavy chains for degradation by mediating their dislocation from the endoplasmic reticulum back into the cytosol, where they are degraded by proteasomes. A functional ubiquitin system is required for US2- and US11-dependent dislocation of the class I heavy chains. It has been assumed that the class I heavy chain itself is ubiquitinated during the dislocation reaction. To test this hypothesis, all lysines within the class I heavy chain were substituted. The lysine-less class I molecules could no longer be dislocated by US2 despite the fact that the interaction between the two proteins was maintained. Interestingly, US11 was still capable of dislocating the lysine-less heavy chains into the cytosol. Ubiquitination does not necessarily require lysine residues but can also occur at the N terminus of a protein. To investigate the potential role of N-terminal ubiquitination in heavy chain dislocation, a lysine-less ubiquitin moiety was fused to the N terminus of the class I molecule. This lysine-less fusion protein was still dislocated in the presence of US11. Ubiquitination could not be detected in vitro, either for the lysine-less heavy chains or for the lysine-less ubiquitin-heavy chain fusion protein. Our data show that although dislocation of the lysineless class I heavy chains requires a functional ubiquitin system, the heavy chain itself does not serve as the ubiquitin acceptor. This finding sheds new light on the role of the ubiquitin system in the dislocation process.

Received for publication, March 9, 2006 , and in revised form, July 17, 2006.

^* This study was supported by Grant RUL 1998-1791 from the Dutch Cancer Society (to G. C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 31-71-526-3932; Fax: 31-71-524-8148; E-mail: wiertz{at}lumc.nl.

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