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Molecular and Cellular Biology, August 2003, p. 5651-5663, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5651-5663.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Phosphorylation of the {alpha} Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-{kappa}B in Response to Diverse Cellular Stresses

Hao-Yuan Jiang,1 Sheree A. Wek,1 Barbara C. McGrath,2 Donalyn Scheuner,3 Randal J. Kaufman,3 Douglas R. Cavener,2 and Ronald C. Wek1*

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202,1 Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802,2 Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 481093

Received 6 March 2003/ Returned for modification 14 April 2003/ Accepted 28 May 2003

Nuclear factor {kappa}B (NF-{kappa}B) serves to coordinate the transcription of genes in response to diverse environmental stresses. In this report we show that phosphorylation of the {alpha} subunit of eukaryotic initiation factor 2 (eIF2) is fundamental to the process by which many stress signals activate NF-{kappa}B. Phosphorylation of this translation factor is carried out by a family of protein kinases that each respond to distinct stress conditions. During impaired protein folding and assembly in the endoplasmic reticulum (ER), phosphorylation of eIF2{alpha} by PEK (Perk or EIF2AK3) is essential for induction of NF-{kappa}B transcriptional activity. The mechanism by which NF-{kappa}B is activated during ER stress entails the release, but not the degradation, of the inhibitory protein I{kappa}B. During amino acid deprivation, phosphorylation of eIF2{alpha} by GCN2 (EIF2AK4) signals the activation of NF-{kappa}B. Furthermore, inhibition of general translation or transcription by cycloheximide and actinomycin D, respectively, elicits the eIF2{alpha} phosphorylation required for induction of NF-{kappa}B. Together, these studies suggest that eIF2{alpha} kinases monitor and are activated by a range of stress conditions that affect transcription and protein synthesis and assembly, and the resulting eIF{alpha} phosphorylation is central to activation of the NF-{kappa}B. The absence of NF-{kappa}B-mediated transcription and its antiapoptotic function provides an explanation for why eIF2{alpha} kinase deficiency in diseases such as Wolcott-Rallison syndrome leads to cellular apoptosis and disease.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Rm. 4053, 635 Barnhill Dr., Indianapolis, IN 46202. Phone: (317) 274-0549. Fax: (317) 274-4686. E-mail: rwek{at}iupui.edu.

Molecular and Cellular Biology, August 2003, p. 5651-5663, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5651-5663.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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