title: Modulation of Kaposi's sarcoma-associated herpesvirus interleukin-6 function by hypoxia-upregulated protein 1.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) is linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV expresses several proteins that modulate host cell signaling pathways. One of these proteins is viral interleukin-6 (vIL-6), which is a homolog of human IL-6 (hIL-6). vIL-6 is able to prevent apoptosis and promote proinflammatory signaling, angiogenesis, and cell proliferation. Although it can be secreted, vIL-6 is mainly an intracellular protein that is retained in the endoplasmic reticulum (ER). We performed affinity purification and mass spectrometry to identify novel vIL-6 binding partners and found that a cellular ER chaperone, hypoxia-upregulated protein 1 (HYOU1), interacts with vIL-6. Immunohistochemical staining reveals that both PEL and KS tumor tissues express significant amounts of HYOU1. We also show that HYOU1 increases endogenous vIL-6 protein levels and that HYOU1 facilitates vIL-6-induced JAK/STAT signaling, migration, and survival in endothelial cells. Furthermore, our data suggest that HYOU1 also modulates vIL-6's ability to induce CCL2, a chemokine involved in cell migration. Finally, we investigated the impact of HYOU1 on cellular hIL-6 signaling. Collectively, our data indicate that HYOU1 is important for vIL-6 function and may play a role in the pathogenesis of KSHV-associated cancers.
  
  
  OBJECTIVE
  KSHV vIL-6 is detectable in all KSHV-associated malignancies and promotes tumorigenesis and inflammation. We identified a cellular protein, called hypoxia-upregulated protein 1 (HYOU1), that interacts with KSHV vIL-6 and is present in KSHV-infected tumors. Our data suggest that HYOU1 facilitates the vIL-6-induced signaling, migration, and survival of endothelial cells.
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Giffin
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ben Major
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA damania@med.unc.edu.
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
mesh_terms: D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006566:Herpesviridae Infections / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; D050791:STAT Transcription Factors; D014764:Viral Proteins; C050087:oxygen-regulated proteins; D053612:Janus Kinases