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J. Biol. Chem., Vol. 281, Issue 4, 1876-1884, January 27, 2006
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1
From the
Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263 and Departments of Medicine and Microbiology and Immunology, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214
Interferon signaling pathways are critical to both innate and adaptive immunity. We have demonstrated here that the inhibition of heat shock protein 90 (Hsp90) functions by small interfering RNAs or chemical inhibitors blocking interferon-induced gene expression. Hsp90 was required for signal transducers and activators of transcription 1 phosphorylation, and in its absence, Janus kinase (JAK) 1/2 were degraded by the proteosome. JAK1 interacts with Hsp90 and the CDC37 co-chaperone, and both interactions are destabilized by Hsp90 inhibitors. The biological consequences were suggested by experiments showing that T cell activation by interferon-
-primed macrophages and the antiviral response of interferons required Hsp90. We conclude that JAK1/2 are client proteins of Hsp90 and that Hsp90 and CDC37 play a critical role in types I and II interferon pathways.
Received for publication, September 8, 2005 , and in revised form, October 25, 2005.
* This study was supported by National Institutes of Health Grant HD17013. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental text, Table I, and Figs. S1 and S2.
1 To whom correspondence should be addressed: Roswell Park Cancer Inst., Elm & Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-3384; Fax: 716-845-8695; E-mail: thomas.tomasi{at}roswellpark.org.
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