Glycosylation of KSHV encoded vGPCR functions in its signaling and tumorigenicity

Viruses. 2015 Mar 31;7(4):1627-41. doi: 10.3390/v7041627.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a tumor virus and the etiologic agent of Kaposi's Sarcoma (KS). KSHV G protein-coupled receptor (vGPCR) is an oncogene that is implicated in malignancies associated with KHSV infection. In this study, we show that vGPCR undergoes extensive N-linked glycosylation within the extracellular domains, specifically asparagines 18, 22, 31 and 202. An immunofluorescence assay demonstrates that N-linked glycosylation are necessary for vGPCR trafficking to the cellular membrane. Employing vGPCR mutants whose glycosylation sites were ablated, we show that these vGPCR mutants failed to activate downstream signaling in cultured cells and were severely impaired to induce tumor formation in the xenograph nude mouse model. These findings support the conclusion that glycosylation is critical for vGPCR tumorigenesis and imply that chemokine regulation at the plasma membrane is crucial for vGPCR mediated signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis*
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Glycosylation
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / physiology*
  • Heterografts / pathology
  • Mice
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Oncogenes*
  • Protein Transport
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Sarcoma, Kaposi / pathology
  • Sarcoma, Kaposi / virology
  • Signal Transduction*

Substances

  • G protein-coupled receptor, Human herpesvirus 8
  • Mutant Proteins
  • Receptors, Chemokine