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Papers In Press, published online ahead of print July 10, 2003
Medicine Dept., The Ohio State University, Columbus, OH 43210
Corresponding Author: xia-3{at}medctr.osu.edu
Nitric oxide (NO) generated by inducible NO synthase (iNOS) plays crucial roles in inflammation and host defense. With an intrinsically bound calmodulin, iNOS is fully active once expressed in cells. Thus, regulation of NO production from iNOS was thought to primarily occur at enzyme transcriptional level. Here we show that NO synthesis from iNOS can be profoundly modulated by heat shock protein 90 (hsp90) through protein-protein interaction. To study whether hsp90 affects iNOS function, recombinant murine iNOS was purified from an E. coli expression system by affinity chromatography. Hsp90, at physiological concentrations (10-500 nM), dose-dependently increased iNOS activity. This was a specific effect because neither denatured hsp90 nor irrelevant bovine serum albumin affected iNOS function. Overexpression of hsp90 enhanced NO production in iNOS-transfected cells. On the contrary, hsp90 inhibition dramatically decreased NO formation from iNOS in macrophages. Co-immunoprecipitation studies showed that hsp90 and iNOS associated each other in cells. Overexpression of iNOS resulted in NO-mediated cellular injury. Hsp90 inhibition markedly attenuated NO formation and prevented cellular injury. These results demonstrated that hsp90 is an allosteric enhancer of iNOS. iNOS is coupled with hsp90 in cells and this coupling facilitates NO synthesis. In light of the critical role of hsp90 in iNOS-mediated cytotoxic action, modulating the interaction between hsp90 and iNOS may be a new approach to intervene inflammation and immune response.
J. Biol. Chem, 10.1074/jbc.M305214200
Submitted on May 19, 2003
Revised on June 25, 2003
Accepted on July 10, 2003
Heat shock protein 90 as an endogenous protein enhancer of inducible nitric oxide synthase
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