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Journal of Virology, June 2007, p. 6573-6583, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02751-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Kaposi's Sarcoma-Associated Herpesvirus K5 E3 Ubiquitin Ligase Modulates Targets by Multiple Molecular Mechanisms{triangledown}

Robert E. Means,1* Sabine M. Lang,1 and Jae U. Jung2

Department of Pathology, Yale University School of Medicine, P.O. Box 208023, New Haven, Connecticut 06520,1 Division of Tumor Virology, Harvard Medical School, New England National Primate Research Center, 1 Pine Hill Drive, Southborough, Massachusetts 017722

Received 14 December 2006/ Accepted 26 March 2007

Kaposi's sarcoma-associated herpesvirus encodes two highly related membrane-associated, RING-CH-containing (MARCH) family E3 ubiquitin ligases, K3 and K5, that can down regulate a variety of cell surface proteins through enhancement of their endocytosis and degradation. In this report we present data that while K5 modulation of major histocompatibility complex class I (MHC-I) closely mirrors the mechanisms used by K3, alternative molecular pathways are utilized by this E3 ligase in the down regulation of intercellular adhesion molecule 1 (ICAM-1) and B7.2. Internalization assays demonstrate that down regulation of each target can occur through increased endocytosis from the cell surface. However, mutation of a conserved tyrosine-based endocytosis motif in K5 resulted in a protein lacking the ability to direct an increased rate of MHC-I or ICAM-1 internalization but still able to down regulate B7.2 in a ubiquitin-dependent but endocytosis-independent manner. Further, mutation of two acidic clusters abolished K5-mediated MHC-I degradation while only slightly decreasing ICAM-1 or B7.2 protein destruction. This same mutant abolished detectable ubiquitylation of all targets. These data indicate that while K5 can act as an E3 ubiquitin ligase to directly mediate cell surface molecule destruction, regulation of its targets occurs through multiple pathways, including ubiquitin-independent mechanisms.

* Corresponding author. Mailing address: Dept. of Pathology, Yale University School of Medicine, P.O. Box 208023, New Haven, CT 06520. Phone: (203) 785-6160. Fax: (203) 785-6127. E-mail: Robert.Means{at}Yale.edu

{triangledown} Published ahead of print on 4 April 2007.

Journal of Virology, June 2007, p. 6573-6583, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02751-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cadwell, K., Coscoy, L. (2008). The Specificities of Kaposi's Sarcoma-Associated Herpesvirus-Encoded E3 Ubiquitin Ligases Are Determined by the Positions of Lysine or Cysteine Residues within the Intracytoplasmic Domains of Their Targets. J. Virol. 82: 4184-4189 [Abstract] [Full Text]  


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