Human herpesvirus 8 interleukin-6 interacts with calnexin cycle components and promotes protein folding

Daming Chen, Qiwang Xiang, John Nicholas

Research output: Contribution to journalArticlepeer-review

Abstract

Viral interleukin-6 (vIL-6) encoded by human herpesvirus 8 (HHV-8) is believed to contribute via mitogenic, survival, and angiogenic activities to HHV-8- associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease through autocrine or paracrine mechanisms during latency or productive replication. There is direct evidence that vIL-6 promotes latently infected PEL cell viability and proliferation and also viral productive replication in PEL and endothelial cells. These activities are mediated largely through endoplasmic reticulum (ER)-localized vIL-6, which can induce signal transduction via the gp130 signaling receptor, activating mitogen-activated protein kinase and signal transducer and activator of transcription signaling, and interactions of vIL-6 with the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). The latter functional axis involves suppression of proapoptotic lysosomal protein cathepsin D by promotion of the ER-associated degradation of ER-transiting, preproteolytically processed procathepsin D. Other interactions of VKORC1v2 and activities of vIL-6 via the receptor have not been reported. We show here that both vIL-6 and VKORC1v2 interact with calnexin cycle proteins UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), which catalyzes monoglucosylation of N-glycans, and oppositely acting glucosidase II (GlucII), and that vIL-6 can promote protein folding. This activity was found to require VKORC1v2 and UGGT1, to involve vIL-6 associations with VKORC1v2, UGGT1, and GlucII, and to operate in the context of productively infected cells. These findings document new VKORC1v2-associated interactions and activities of vIL-6, revealing novel mechanisms of vIL-6 function within the ER compartment.

Original languageEnglish (US)
Article numbere00965-17
JournalJournal of virology
Volume91
Issue number22
DOIs
StatePublished - Nov 1 2017

Keywords

  • Calnexin cycle
  • Endoplasmic reticulum
  • Glucosidase II
  • Human herpesvirus 8
  • Protein folding
  • UDP-glucose:glycoprotein glucosyltransferase 1
  • VKORC1v2
  • Viral interleukin-6

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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