Back to Search
Start Over
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.
- Source :
-
Journal of virology [J Virol] 2014 Jan; Vol. 88 (2), pp. 1025-38. Date of Electronic Publication: 2013 Nov 06. - Publication Year :
- 2014
-
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.
- Subjects :
- Apoptosis
Cathepsin D metabolism
Cell Survival
Down-Regulation
Herpesvirus 8, Human genetics
Humans
Interleukin-6 genetics
Lymphoma, Primary Effusion genetics
Lymphoma, Primary Effusion virology
Protein Binding
Viral Proteins genetics
Vitamin K Epoxide Reductases genetics
Cathepsin D genetics
Herpesvirus 8, Human metabolism
Interleukin-6 metabolism
Lymphoma, Primary Effusion enzymology
Lymphoma, Primary Effusion physiopathology
Viral Proteins metabolism
Vitamin K Epoxide Reductases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 88
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 24198402
- Full Text :
- https://doi.org/10.1128/JVI.02830-13