Molecular Mechanisms for Viral Mimicry of a Human Cytokine: Activation of gp130 by HHV-8 Interleukin-6

Martin J. Boulanger, Dar Chone Chow, Elena Brevnova, Monika Martick, Gordon Sandford, John Nicholas, K. Christopher Garcia

Research output: Contribution to journalArticle

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV, or HHV-8) encodes a pathogenic viral homologue of human interleukin-6 (IL-6). In contrast to human IL-6 (hIL-6), viral IL-6 (vIL-6) binds directly to, and activates, the shared human cytokine signaling receptor gp130 without the requirement for pre-complexation to a specific α-receptor. Here, we dissect the biochemical and functional basis of vIL-6 mimicry of hIL-6. We find that, in addition to the "α-receptor-independent" tetrameric vIL-6/gp130 complex, the viral cytokine can engage the human α-receptor (IL-6Rα) to form a hexameric vIL-6/IL-6Rα/gp130 complex with enhanced signaling potency. In contrast to the assembly sequence of the hIL-6 hexamer, the preformed vIL-6/gp130 tetramer can be decorated with IL-6Rα, post facto, in a "vIL-6-dependent" fashion. A detailed comparison of the viral and human cytokine/gp130 interfaces indicates that vIL-6 has evolved a unique molecular strategy to interact with gp130, as revealed by an almost entirely divergent structural makeup of its receptor binding sites. Viral IL-6 appears to utilize an elegant combination of both convergent, and unexpectedly divergent, molecular strategies to oligomerize gp130 and activate similar downstream signaling cascades as its human counterpart.

Original languageEnglish (US)
Pages (from-to)641-654
Number of pages14
JournalJournal of molecular biology
Volume335
Issue number2
DOIs
StatePublished - Jan 9 2004

Keywords

  • KSHV/HHV-8
  • Molecular mimicry
  • Protein-protein interactions
  • Viral pathogenesis
  • gp130

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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