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Journal of Virology, May 2009, p. 5117-5126, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.01601-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Unraveling Viral Interleukin-6 Binding to gp130 and Activation of STAT-Signaling Pathways Independently of the Interleukin-6 Receptor{triangledown} ,{ddagger}

Nina Adam,{dagger} Björn Rabe,{dagger},§ Jan Suthaus, Joachim Grötzinger, Stefan Rose-John,* and Jürgen Scheller*

Institute of Biochemistry, Christian Albrechts University of Kiel, Kiel, Germany

Received 28 July 2008/ Accepted 20 February 2009

Human herpesvirus 8 encodes a viral version of interleukin-6 (vIL-6) which shows 25% sequence homology with human IL-6. In contrast to human IL-6, which first binds to the IL-6 receptor (IL-6R) and only subsequently associates with the signal transducing receptor subunit gp130, vIL-6 has been shown to directly bind to gp130 without the need of IL-6R. As a functional consequence, vIL-6 can activate far more target cells in the body since all cells express gp130, but only cells such as hepatocytes and some leukocytes express IL-6R. We sought to understand which amino acid sequences within the vIL-6 protein were responsible for its ability to bind and activate gp130 independent of IL-6R. As a first approach, we constructed chimeric IL-6 proteins in which all known gp130 interacting sites (sites II and III) were sequentially transferred from vIL-6 into the human IL-6 protein. To our surprise, human IL-6 carrying all gp130 interacting sites from vIL-6 did not show IL-6R-independent gp130 activation. Even more surprisingly, the loop between helix B and C of vIL-6, clearly shown in the crystal structure not to be in contact with gp130, is indispensable for direct binding to and activation of gp130. This points to an IL-6R induced change of site III conformation in human IL-6, which is already preformed in vIL-6. These data indicate a novel activation mechanism of human IL-6 by the IL-6R that will be important for the construction of novel hyperactive cytokine variants.

* Corresponding author. Mailing address: Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany. Phone for Jürgen Scheller: 49-431-880 1676. Fax: 49-431-880 5007. E-mail: jscheller{at}biochem.uni-kiel.de. Phone for Stefan Rose-John: 49-431-880 3336. Fax: 49-431-880 5007. E-mail: rosejohn{at}biochem.uni-kiel.de

{triangledown} Published ahead of print on 4 March 2009.

{ddagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{dagger} N.A. and B.R. contributed equally to this study.

§ Present address: MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.

Journal of Virology, May 2009, p. 5117-5126, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.01601-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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