Human herpesvirus 8 interleukin-6 (vIL-6) signals through gp130 but has structural and receptor-binding properties distinct from those of human IL-6.
Human herpesvirus 8 (HHV-8) has been associated with classical, endemic (African), and AIDS-related Kaposi's sarcoma (KS), body cavity-based primary effusion lymphomas, and multicentric Castleman's disease (MCD). HHV-8 encodes a functional homologue of interleukin-6 (IL-6), a cytokine that promotes the growth of KS and myeloma cells and is found at elevated levels in MCD lesions and patient sera. We have previously reported that the viral IL-6 (vIL-6) gene product can support the growth of the IL-6-dependent murine hybridoma cell line, B9, and that the gp80 (IL-6 receptor [IL-6R]) component of the IL-6 receptor-signal transducer (gp180) complex plays a role in mediating this activity. However, it has been shown by others that vIL-6 can function in human cells independently of IL-6R. Here we have extended our functional studies of vIL-6 by identifying transcription factors and pathways used in human Hep3B cells, investigating the utilization of gp130 and IL-6R by vIL-6, and undertaking mutational analyses of vIL-6 and gp130. The data presented here establish that vIL-6, in common with its endogenous counterparts, can mediate signal transduction through gp130 and activate multiple transcription factors, map residues within the vIL-6 protein that are and are not important for vIL-6 signalling, and identify a gp130 mutant that is nonfunctional with respect to vIL-6 signalling in the absence of IL-6R but that retains the ability to mediate vIL-6 and human IL-6 (hIL-6) signal transduction when IL-6R is coexpressed. The data presented demonstrate functional and mechanistic similarities between vIL-6 and endogenous IL-6 proteins but also highlight differences in the structural and receptor-binding properties of vIL-6 relative to its human counterpart.
Wan
X
X
Molecular Virology Laboratories, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Wang
H
H
Nicholas
J
J
D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D050822:Cytokine Receptor gp130; D006566:Herpesviridae Infections / Q000378:metabolism* / Q000503:physiopathology; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity; D014764:Viral Proteins / Q000378:metabolism*
D015703:Antigens, CD; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D014764:Viral Proteins; D050822:Cytokine Receptor gp130