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Molecular and Cellular Biology, December 2004, p. 10161-10168, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10161-10168.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Translational Repression Mediates Activation of Nuclear Factor Kappa B by Phosphorylated Translation Initiation Factor 2

Jing Deng,1 Phoebe D. Lu,1 Yuhong Zhang,1 Donalyn Scheuner,2 Randal J. Kaufman,2,3 Nahum Sonenberg,4 Heather P. Harding,5 and David Ron1*

Skirball Institute of Biomolecular Medicine,1 Departments of Cell Biology, Medicine, and Pharmacology, New York University School of Medicine, New York, New York,5 Department of Biochemistry,2 Howard Hughes Medical Institute, University of Michigan School of Medicine, Ann Arbor, Michigan,3 Department of Biochemistry, McGill University, Montreal, Quebec, Canada4

Received 11 May 2004/ Returned for modification 6 July 2004/ Accepted 31 August 2004

Numerous stressful conditions activate kinases that phosphorylate the alpha subunit of translation initiation factor 2 (eIF2{alpha}), thus attenuating mRNA translation and activating a gene expression program known as the integrated stress response. It has been noted that conditions associated with eIF2{alpha} phosphorylation, notably accumulation of unfolded proteins in the endoplasmic reticulum (ER), or ER stress, are also associated with activation of nuclear factor kappa B (NF-{kappa}B) and that eIF2{alpha} phosphorylation is required for NF-{kappa}B activation by ER stress. We have used a pharmacologically activable version of pancreatic ER kinase (PERK, an ER stress-responsive eIF2{alpha} kinase) to uncouple eIF2{alpha} phosphorylation from stress and found that phosphorylation of eIF2{alpha} is both necessary and sufficient to activate both NF-{kappa}B DNA binding and an NF-{kappa}B reporter gene. eIF2{alpha} phosphorylation-dependent NF-{kappa}B activation correlated with decreased levels of the inhibitor I{kappa}B{alpha} protein. Unlike canonical signaling pathways that promote I{kappa}B{alpha} phosphorylation and degradation, eIF2{alpha} phosphorylation did not increase phosphorylated I{kappa}B{alpha} levels or affect the stability of the protein. Pulse-chase labeling experiments indicate instead that repression of I{kappa}B{alpha} translation plays an important role in NF-{kappa}B activation in cells experiencing high levels of eIF2{alpha} phosphorylation. These studies suggest a direct role for eIF2{alpha} phosphorylation-dependent translational control in activating NF-{kappa}B during ER stress.

* Corresponding author. Mailing address: New York University Medical Center, SI 3-10, 540 First Ave., New York, NY 10016. Phone: (212) 263-7786. Fax: (212) 263-8951. E-mail: ron{at}saturn.med.nyu.edu.

Molecular and Cellular Biology, December 2004, p. 10161-10168, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10161-10168.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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