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N-linked glycosylation is required for optimal function of Kaposi's sarcoma herpesvirus-encoded, but not cellular, interleukin 6.

Dela Cruz CS, Lee Y, Viswanathan SR, El-Guindy AS, Gerlach J, Nikiforow S, Shedd D, Gradoville L, Miller G - J. Exp. Med. (2004)

Bottom Line: 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.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.These findings highlight distinct functional roles of N-linked glycosylation in viral and cellular IL-6.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
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.

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Fully glycosylated hIL-6 is more potent than the KSHV IL-6 counterpart. 10-fold serially diluted supernatants from HKB5/B5 cells transfected with plasmids encoding wild-type hIL-6 or vIL-6, all starting at 10 ng/ml, were assessed for their capacity to stimulate proliferation of B9.11 cells.
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fig11: Fully glycosylated hIL-6 is more potent than the KSHV IL-6 counterpart. 10-fold serially diluted supernatants from HKB5/B5 cells transfected with plasmids encoding wild-type hIL-6 or vIL-6, all starting at 10 ng/ml, were assessed for their capacity to stimulate proliferation of B9.11 cells.

Mentions: To compare the biological activity of cellular IL-6 and vIL-6 that were expressed in mammalian HKB5/B5 cells, we used equal amounts of the fully glycosylated wild-type hIL-6 and vIL-6 to stimulate B9.11 cell proliferation. The fully glycosylated form of hIL-6 was ∼100 times more potent in stimulating the IL-6–dependent cell growth than the fully glycosylated form of vIL-6 (Fig. 11).


N-linked glycosylation is required for optimal function of Kaposi's sarcoma herpesvirus-encoded, but not cellular, interleukin 6.

Dela Cruz CS, Lee Y, Viswanathan SR, El-Guindy AS, Gerlach J, Nikiforow S, Shedd D, Gradoville L, Miller G - J. Exp. Med. (2004)

Fully glycosylated hIL-6 is more potent than the KSHV IL-6 counterpart. 10-fold serially diluted supernatants from HKB5/B5 cells transfected with plasmids encoding wild-type hIL-6 or vIL-6, all starting at 10 ng/ml, were assessed for their capacity to stimulate proliferation of B9.11 cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211829&req=5

fig11: Fully glycosylated hIL-6 is more potent than the KSHV IL-6 counterpart. 10-fold serially diluted supernatants from HKB5/B5 cells transfected with plasmids encoding wild-type hIL-6 or vIL-6, all starting at 10 ng/ml, were assessed for their capacity to stimulate proliferation of B9.11 cells.
Mentions: To compare the biological activity of cellular IL-6 and vIL-6 that were expressed in mammalian HKB5/B5 cells, we used equal amounts of the fully glycosylated wild-type hIL-6 and vIL-6 to stimulate B9.11 cell proliferation. The fully glycosylated form of hIL-6 was ∼100 times more potent in stimulating the IL-6–dependent cell growth than the fully glycosylated form of vIL-6 (Fig. 11).

Bottom Line: 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.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.These findings highlight distinct functional roles of N-linked glycosylation in viral and cellular IL-6.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus