The Journal of Experimental Medicine
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Published 17 February 2004. doi:10.1084/jem.20031205
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 503-514
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N-linked Glycosylation Is Required for Optimal Function of Kaposi's Sarcoma Herpesvirus–encoded, but Not Cellular, Interleukin 6

Charles S. Dela Cruz1, Yoomi Lee1, Srinivas R. Viswanathan1, Ayman S. El-Guindy1, Jennifer Gerlach4, Sarah Nikiforow5, Duane Shedd2, Lyn Gradoville2, and George Miller1,2,3

1 Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06520
2 Department of Pediatrics, Yale School of Medicine, New Haven, CT 06520
3 Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT 06520
4 Department of Microbiology, Yale School of Medicine, New Haven, CT 06520
5 Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520

Address correspondence to George Miller, Department of Pediatrics, Yale University School of Medicine, Room 420 LSOG, 333 Cedar Street, New Haven, CT 06520. Phone: (203) 785-4758; Fax: (203) 785-6961; email: George.Miller{at}Yale.edu

Kaposi's sarcoma–associated herpesvirus interleukin-6 (vIL-6) is a structural and functional homologue of the human cytokine IL-6 (hIL-6). hIL-6 and vIL-6 exhibit similar biological functions and both act via the gp130 receptor subunit to activate the Janus tyrosine kinase (JAK)1 and signal transducer and activator of transcription (STAT)1/3 pathway. Here we show that vIL-6 is N-linked glycosylated at N78 and N89 and demonstrate that N-linked glycosylation at site N89 of vIL-6 markedly enhances binding to gp130, signaling through the JAK1-STAT1/3 pathway and functions in a cytokine-dependent cell proliferation bioassay. Although hIL-6 is also N-glycosylated at N73 and multiply O-glycosylated, neither N-linked nor O-linked glycosylation is necessary for IL-6 receptor {alpha}–dependent binding to gp130 or signaling through JAK1-STAT1/3. As distinct from vIL-6, unglycosylated hIL-6 is as potent as glycosylated hIL-6 in stimulating B cell proliferation. These findings highlight distinct functional roles of N-linked glycosylation in viral and cellular IL-6.

Key Words: IL-6 • viral proteins • glycosylation • KSHV • cytokine

The online version of this article contains supplemental material.

Abbreviations used in this paper: hIL-6, human IL-6; HRP, horseradish peroxidase; JAK, Janus tyrosine kinase; KSHV, Kaposi's sarcoma–associated herpesvirus; PEL, primary effusion lymphoma; STAT, signal transducer and activator of transcription; TM, tunicamycin; vIL-6, viral IL-6.


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