Intracellular Signaling Mechanisms and Activities of Human Herpesvirus 8 Interleukin-6

Abstract

Human herpesvirus 8 (HHV-8)-encoded viral interleukin-6 (vIL-6) has been implicated as a key factor in virus-associated neoplasia because of its proproliferative and survival effects and also in view of its angiogenic properties. A major difference between vIL-6 and human IL-6 (hIL-6) is that vIL-6, uniquely, is largely retained and can signal intracellularly. While vIL-6 is generally considered to be a lytic gene, several reports have noted its low-level expression in latently infected primary effusion lymphoma (PEL) cultures, in the absence of other lytic gene expression. Thus, intracellular autocrine signal transduction by the viral cytokine may be of particular relevance to the growth and survival of latently infected cells and to pathogenesis. Here we report that most intracellular vIL-6 is located in the endoplasmic reticulum (ER), signals via the gp130 signal transducer in this compartment, and does so independently of the gp80 ␣-subunit of the IL-6 receptor, required for hIL-6 signal transduction. Signaling and biological assays incorporating ER-retained vIL-6 and hIL-6 confirmed vIL-6 activity, specifically, in this compartment. Knockdown of vIL-6 expression in PEL cells led to markedly reduced cell growth in normal culture, independently of extracellular cytokines. This could be reversed by reintroduction via virus vector of exclusively ER-retained vIL-6. These data indicate that in virus biology vIL-6 may act to support the growth and survival of cells latently infected with HHV-8 in an autocrine manner via intracrine signaling and that these activities may contribute to the maintenance of latently infected cells and to virus-induced neoplasia.

Human Herpesvirus 8 Viral Interleukin-6 Signaling through gp130 Promotes Virus Replication in Primary Effusion Lymphoma and Endothelial Cells

“…HHV-8-encoded viral interleukin-6 (vIL-6) promotes cell growth and survival, inflammation, and angiogenesis and is implicated in pathogenesis (4)(5)(6)(7)(8)(9). However, its role in normal virus biology remains unclear.…”

“…Human IL-6 forms hexameric signaling complexes comprised of two gp80 receptor subunits, two gp130 signal transducers, and two hIL-6 molecules (gp80 2 -gp130 2 -IL-6 2 ) (10). Viral IL-6 can also form signaling hexamers at the cell surface, but its unique signaling from the endoplasmic reticulum (ER) occurs via tetrameric complexes (gp130 2 -vIL-6 2 ) exclusively (8,12,15,16). Viral IL-6 can be expressed during latent stages, in addition to lytic stages, of the viral life cycle (8,17).…”

“…Viral IL-6 can also form signaling hexamers at the cell surface, but its unique signaling from the endoplasmic reticulum (ER) occurs via tetrameric complexes (gp130 2 -vIL-6 2 ) exclusively (8,12,15,16). Viral IL-6 can be expressed during latent stages, in addition to lytic stages, of the viral life cycle (8,17). Latently infected PEL cell viability is maintained in part via vIL-6/gp130 signaling from the ER and also through its interaction with vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2) (7,18); the latter contributes to productive replication as well (19).…”

“…The gp130 signal transducer was depleted in TRExBCBL1-replication and transcription activator (RTA) and JSC-1 PEL cells (26,27) and in TIME-TRE/RTA endothelial cells (28) latently infected with HHV-8 r219 (29) using previously established techniques (7,8). Following depletion, lytic replication was induced with doxycycline (Dox) or 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate (NaB).…”

Pathogenetic Influences of Human Herpesvirus 8 (HHV-8) in Prostate Cancer Progression

“…The viral G protein-couple receptor (vGPCR) is a lytic protein that promotes cellular proliferation by simultaneously activating several signal transduction pathways, including MAPK, AKT and the transcription factor NF-κB (116)(117)(118). A second lytic protein, viral IL-6 (vIL-6) is a structural and functional homolog to cellular IL-6 (119) and through activation of the STAT3 pathway also contributes to cellular growth (120,121).…”