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Molecular and Cellular Biology, September 1999, p. 5861-5871, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Dual Role for Hsc70 in the Biogenesis and Regulation of the Heme-Regulated Kinase of the alpha  Subunit of Eukaryotic Translation Initiation Factor 2

Sheri Uma, Vanitha Thulasiraman,dagger and Robert L. Matts*

Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma 74078-3035

Received 25 February 1999/Returned for modification 26 March 1999/Accepted 29 May 1999

The heme-regulated kinase of the alpha  subunit of eukaryotic initiation factor 2 (HRI) is activated in rabbit reticulocyte lysate (RRL) in response to a number of environmental conditions, including heme deficiency, heat shock, and oxidative stress. Activation of HRI causes an arrest of initiation of protein synthesis. Recently, we have demonstrated that the heat shock cognate protein Hsc70 negatively modulates the activation of HRI in RRL in response to these environmental conditions. Hsc70 is also known to be a critical component of the Hsp90 chaperone machinery in RRL, which plays an obligatory role for HRI to acquire and maintain a conformation that is competent to activate. Using de novo-synthesized HRI in synchronized pulse-chase translations, we have examined the role of Hsc70 in the regulation of HRI biogenesis and activation. Like Hsp90, Hsc70 interacted with nascent HRI and HRI that was matured to a state which was competent to undergo stimulus-induced activation (mature-competent HRI). Interaction of HRI with Hsc70 was required for the transformation of HRI, as the Hsc70 antagonist clofibric acid inhibited the folding of HRI into a mature-competent conformation. Unlike Hsp90, Hsc70 also interacted with transformed HRI. Clofibric acid disrupted the interaction of Hsc70 with transformed HRI that had been matured and transformed in the absence of the drug. Disruption of Hsc70 interaction with transformed HRI in heme-deficient RRL resulted in its hyperactivation. Furthermore, activation of HRI in response to heat shock or denatured proteins also resulted in a similar blockage of Hsc70 interaction with transformed HRI. These results indicate that Hsc70 is required for the folding and transformation of HRI into an active kinase but is subsequently required to negatively attenuate the activation of transformed HRI.

* Corresponding author. Mailing address: 246 NRC, Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078-3035. Phone: (405) 744-6200. Fax: (405) 744-7799. E-mail: rlmatts{at}okway.okstate.edu.

dagger Present address: Department of Biological Sciences, Stanford University, Stanford, CA 94305.

Molecular and Cellular Biology, September 1999, p. 5861-5871, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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