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B Signaling Pathway Results from the Insolubilization of the IB Kinase Complex following Its Dissociation from Heat Shock Protein 901
* Laboratory of Surgical Research, Departments of Anesthesia and Surgery, University of California, San Francisco, CA 94110; and
Gladstone Institute of Virology and Immunology, San Francisco, CA 94158
Activation of the stress response attenuates proinflammatory responses by suppressing cytokine-stimulated activation of the NF-
B signaling pathway. In this study, we show that the activation of the cellular stress response, either by heat shock treatment or after exposure to sodium arsenite, leads to a transient inhibition of IB
phosphorylation. Inhibition of IB phosphorylation after stress was associated with the detergent insolubilization of the upstream kinases, IB kinase (IKK) and IB kinase 
, components involved in IB phosphorylation. Pretreatment of cells with glycerol, a chemical chaperone that reduces the extent of stress-induced protein denaturation, reduced the stress-dependent detergent insolubility of the IKK complex and restored the cytokine-stimulated phosphorylation of IB. The stress-dependent insolubility of the IKK complex appeared reversible; as the cells recovered from the heat shock treatment, the IKK complex reappeared within the soluble fraction of cells and was again capable of mediating the phosphorylation of IB in response to added cytokines. Treatment of cells with geldanamycin, an inhibitor of heat shock protein 90 (Hsp90) function, also resulted in IKK detergent insolubility and proteasome-mediated degradation of the IKK complex. Furthermore, while IKK coprecipitated with Hsp90 in control cells, coprecipitation of the two proteins was greatly reduced in those cells early after stress or following exposure to geldanamycin. Stress-induced transient insolubilization of the IB kinase complex following its dissociation from Hsp90 represents a novel mechanism by which the activation of the stress response inhibits the NF-B signaling pathway in response to proinflammatory stimuli.
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