Human herpesvirus 8 (HHV-8) specifies a homologue of interleukin-6, vIL-6, which is implicated in the development and progression of HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). We have determined that in PEL cells vIL-6 is expressed at low but functional levels during latency;vIL-6 in this setting supports cell growth and survival, and these functions are mediated predominantly intracellularly by vIL-6 localized in the endoplasmic reticulum (ER). Thus, intracrine, strictly autocrine signaling by vIL-6 is likely to be an important contributor to PEL disease and represents a unique mode of cytokine activity in disease pathogenesis. The mechanisms underlying this activity of vIL-6 in PEL cells is not understood, but we have identified a functionally important interaction of vIL-6 with a novel protein, vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2), and also have recently determined that the IL-6 signal transducer, gp130, is essential for sustained growth of PEL cells. Additionally, we have identified interactions of VKORC1v2 with thioredoxin reductase-like protein 1 (TMX1), protein disulfide isomerase A6/P5 (PDI-A6) and cathepsin D (catD) that suggest possible functions of VKORC1v2 related to vIL-6 folding and/or influence of vIL-6, via VKORC1v2 interaction, on ER stress responses or on catD processing and associated regulation of pro-proliferative and apoptotic signaling. In this R21 application, we propose to identify and test in respect of PEL inhibition peptide and small molecule inhibitors of vIL- 6:VKORC1v2 interaction and functional vIL-6:gp130 complexing;we will also assess the effects of validated inhibitors on functions predicted from interaction of VKORC1v2 with its newly identified cellular interaction partners. The work therefore extends our functional characterization of vIL-6 interactions with VKORC1v2 and gp130 in the context of PEL and addresses molecular strategies to target these biologically important virus- host interactions. The project has substantial significance to the future development of drug-based therapies for this and possibly other HHV-8-associated malignancies in which vIL-6 is likely to play a critical role.
Human herpesvirus 8 (HHV-8) encodes a cytokine homologue, viral interleukin-6 (vIL-6), that is believed to be a key contributor to HHV-8-associated malignancies Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). In PEL cells, vIL-6 interacts with cellular signal transducer gp130 and a largely uncharacterized protein called vitamin K epoxide reductase complex subunit 1 variant-2 (VKORC1v2), both of which are important for PEL cell growth and survival. The project outlined in this application is focused on characterization of functionally relevant interactions of vIL-6 with these cellular targets and the identification of compounds that disrupt these interactions in order to provide the basis for future development of therapies for PEL and possibly KS and MCD also.
| Cousins, Emily; Nicholas, John (2014) Molecular biology of human herpesvirus 8: novel functions and virus-host interactions implicated in viral pathogenesis and replication. Recent Results Cancer Res 193:227-68 |
