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Journal of Virology, July 2009, p. 6874-6882, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02625-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Determinants of Secretion and Intracellular Localization of Human Herpesvirus 8 Interleukin-6{triangledown}

Daming Chen, Young Bong Choi, Gordon Sandford, and John Nicholas*

Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Received 19 December 2008/ Accepted 14 April 2009

Human herpesvirus 8 (HHV-8) interleukin-6 (vIL-6) is distinct from human and other cellular IL-6 proteins in that it does not require the nonsignaling {alpha}-receptor subunit for the formation of gp130-based signal transducing complexes and also is largely retained intracellularly rather than being secreted. We and others have reported that vIL-6 is retained and is active in the endoplasmic reticulum (ER) compartment, and data from our laboratory have demonstrated that intracellular vIL-6 is functional in the autocrine promotion of proliferation and survival of HHV-8 latently infected primary effusion lymphoma cells. It has also been reported that vIL-6 secretion in gp130-deficient cells can be enhanced by introduced gp130, thereby implicating the signal transducer in vIL-6 trafficking to the cell surface. We examine here the requirements for intracellular retention and localization of vIL-6. Using vIL-6-hIL-6 chimeric and point-mutated vIL-6 proteins, we identified regions and residues of vIL-6 influencing vIL-6 secretion. However, there was no correlation between vIL-6 secretion and gp130 interaction. We found that vIL-6, but not hIL-6, could associate stably with ER-resident chaperone protein calnexin. Glycosylation-dependent interaction of vIL-6 with calnexin correlated with proper protein folding, but there was no direct relationship between vIL-6-calnexin interaction and intracellular retention. While calnexin depletion had little influence on absolute amounts of secreted vIL-6, it led to markedly reduced levels of intracellular cytokine. This was reversed by gp130 transduction, which had no detectable effect on vIL-6 secretion, but redistributed vIL-6 into ER-distinct locations in calnexin-depleted cells, specifically. Our data reveal that calnexin plays a role in ER localization of vIL-6 and that gp130 promotes ER exit, but not secretion, of the viral cytokine.

* Corresponding author. Mailing address: Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St., Rm. 309, Baltimore, MD 21287. Phone: (410) 502-6801. Fax: (410) 502-6802. E-mail: nichojo{at}jhmi.edu

{triangledown} Published ahead of print on 22 April 2009.

Journal of Virology, July 2009, p. 6874-6882, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.02625-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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