Kaposi's sarcoma-associated herpesvirus-encoded viral interleukin-6 is secreted and modified differently than human interleukin-6: evidence for a unique autocrine signaling mechanism.
Viral interleukin-6 (vIL-6) is a homolog of cellular IL-6 that is encoded by the Kaposi's sarcoma-associated herpesvirus (KSHV) genome. vIL-6 binds to the IL-6 signal transducer gp130 without the cooperation of the IL-6 high affinity receptor to induce STAT3 DNA binding and cell proliferation. Although vIL-6 is believed to be important in the pathogenesis of KSHV-induced diseases, its secretion and post-translational modifications have not previously been characterized. Pulse-chase analysis revealed that the half-time of vIL-6 secretion is approximately 8-fold longer than that of human IL-6. Yet, the vIL-6 signal sequence targets human IL-6 secretion to nearly wild-type levels. Surprisingly, vIL-6 was not secreted from a cell line that does not express gp130 but expression of human gp130 in these cells enabled the secretion of vIL-6. Consistent with this observation, complete maturation of gp130 N-glycans is inhibited by vIL-6 coexpression, suggesting that the binding of the receptor to vIL-6 occurs intracellularly in early or pre-Golgi compartments. Furthermore, a vIL-6 mutant containing an endoplasmic reticulum retention signal is not secreted but does still induce receptor activation and signaling. Secreted vIL-6 is completely glycosylated at both possible N-glycosylaton sites and contains a large proportion of immature high-mannose glycans that is not typical of cytokines. These findings suggest that vIL-6 may induce gp130 signaling by an exclusively autocrine mechanism that relies on intracellular binding to its receptor. During KSHV infection, vIL-6 may only induce signaling in KSHV-infected cells to benefit the viral life cycle and promote oncogenic transformation.
Meads
Mark B
MB
Medveczky
Peter G
PG
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D019898:Autocrine Communication; D001483:Base Sequence; D002460:Cell Line; D050822:Cytokine Receptor gp130; D004279:DNA, Viral / Q000235:genetics; D006031:Glycosylation; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D004279:DNA, Viral; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D050822:Cytokine Receptor gp130