title: Human herpesvirus 8 interleukin-6 contributes to primary effusion lymphoma cell viability via suppression of proapoptotic cathepsin D, a cointeraction partner of vitamin K epoxide reductase complex subunit 1 variant 2.
abstract: Human herpesvirus 8 (HHV-8) interleukin-6 (vIL-6) promotes cell proliferation and survival and is proangiogenic, implicating it as a contributor to virus-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Although predominantly lytically expressed, vIL-6 is also produced at low, functional levels during latency in PEL cells. Unlike other IL-6 cytokines, vIL-6 is secreted very inefficiently and localizes in the endoplasmic reticulum (ER). ER-localized vIL-6 supports PEL cell proliferation and survival, mediated in part through its interaction with the largely uncharacterized ER-resident protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). Here, we report that the ER-transiting and functionally mitogenic secreted proenzyme (pCatD) form of cathepsin D (mature CatD), a proapoptotic lysosomal aspartate protease, is an interaction partner of VKORC1v2 and that vIL-6 promotes this interaction. Depletion of vIL-6 in PEL cells increased levels of the catalytically active, proteolytically cleaved form of CatD, corresponding with decreased PEL cell viability. Ectopic expression of CatD in PEL cells induced apoptosis, suggesting that CatD suppression by vIL-6 is biologically significant. In the context of high-density culture or reactivation of HHV-8 lytic replication in PEL cells, CatD depletion substantially reduced stress-induced apoptosis and increased virus production. In contrast, CatD overexpression, vIL-6 depletion, and peptide-mediated disruption of vIL-6-VKORC1v2 interaction inhibited replication and cell survival. Combined, our data identify pCatD as an interaction partner of VKORC1v2, demonstrate a role of vIL-6 in CatD suppression via VKORC1v2 in PEL cells, and identify a biologically significant mechanism of vIL-6 prosurvival and proreplication activities via VKORC1v2.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Daming
authors.initials: D
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: John
authors.initials: J
authors.lastname: Nicholas
mesh_terms: D017209:Apoptosis; D002402:Cathepsin D / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D015536:Down-Regulation; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D054685:Lymphoma, Primary Effusion / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology* / Q000821:virology; D011485:Protein Binding; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D014764:Viral Proteins; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D002402:Cathepsin D