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Multiple endocytic trafficking pathways of MHC class I molecules induced by a Herpesvirus protein

Robert E. Means, Satoshi Ishido, Xavier Alvarez, Jae U. Jung

Author Affiliations

  1. Robert E. Means1,
  2. Satoshi Ishido2,
  3. Xavier Alvarez3 and
  4. Jae U. Jung*,1
  1. 1 Department of Microbiology and Molecular Genetics, Division of Tumor Virology, Harvard Medical School, One Pine Hill Drive, Southborough, MA, 01772, USA
  2. 2 Department of Microbiology, Kobe University Graduate School of Medicine, 7‐5‐1 Kusunoki‐cho, Chuo‐ku, Kobe, Hyogo, 650‐0017, Japan
  3. 3 Department of Pathology, New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA, 01772, USA
  1. *Corresponding author. E‐mail: jae_jung{at}hms.harvard.edu
  1. R.E.Means and S.Ishido contributed equally to this work

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Abstract

The K3 protein of a human tumor‐inducing herpesvirus, Kaposi's sarcoma‐associated herpesvirus (KSHV), down‐regulates major histocompatibility complex (MHC) class I surface expression by increasing the rate of endocytosis. In this report, we demonstrate that the internalization of MHC class I by the K3 protein is the result of multiple, consecutive trafficking pathways that accelerate the endocytosis of class I molecules, redirect them to the trans‐Golgi network (TGN), and target MHC class I to the lysosomal compartment. Remarkably, these actions of K3 are functionally and genetically separable; the N‐terminal zinc finger motif and the central sorting motif are involved in triggering internalization of MHC class I molecules and redirecting them to the TGN. Subsequently, the C‐terminal diacidic cluster region of K3 is engaged in targeting MHC class I molecules to the lysosomal compartment. These results demonstrate a novel trafficking mechanism of MHC class I molecules induced by KSHV K3, which ensures viral escape from host immune effector recognition.

  • Received August 23, 2001.
  • Revision received January 28, 2002.
  • Accepted February 5, 2002.
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