Abstract
The molecular chaperone Hsp90 affects the function and fate of a number of signaling molecules. We have investigated the Hsp90 requirement for constitutive and inducible activity of the IκB kinase (IKK) complex and of NF-κB. Inhibition by the Hsp90 ATPase inhibitors, geldanamycin (GA) and radicicol (RC), revealed that Hsp90 controls IKKs at two levels, inducibility of enzymatic activity and biogenesis, which can be discriminated by short- and long-time GA incubation, respectively. Short-time inhibition of Hsp90 resulted in impaired IKK kinase activation by TNFα, IL-1β or phorbolester PMA. Furthermore, GA inhibited constitutive activation of IKK and NF-κB in Hodgkin's lymphoma cells. Hsp90 function was also required for trans- and autophosphorylation of transfected IKKβ. GA exposure for several hours resulted in a downmodulation of IKK complex α, β and γ subunits to various extent. Proteasome inhibition interfered with GA mediated IKK depletion and Hsp90 inhibition induced polyubiquitination of IKKα and β during protein synthesis. In fact, GA blocked biogenesis of IKKα and IKKβ but did not interfere with post-translational turnover. Together, these results define a dual requirement for Hsp90 as a regulator of NF-κB signaling by its general involvement in IKK activation and by its role in IKK homeostasis.
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This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (Sche277/7) to CS.
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Broemer, M., Krappmann, D. & Scheidereit, C. Requirement of Hsp90 activity for IκB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-κB activation. Oncogene 23, 5378–5386 (2004). https://doi.org/10.1038/sj.onc.1207705
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DOI: https://doi.org/10.1038/sj.onc.1207705
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