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Molecular and Cellular Biology, August 2009, p. 4295-4307, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00260-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Eukaryotic Translation Initiation Factor 2{alpha} Coordinates rRNA Transcription and Translation Inhibition during Endoplasmic Reticulum Stress{triangledown} ,{dagger}

Jenny B. DuRose,1 Donalyn Scheuner,3 Randal J. Kaufman,3 Lawrence I. Rothblum,2 and Maho Niwa1*

Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0377,1 Department of Cell Biology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104,2 Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 481093

Received 26 February 2009/ Returned for modification 1 April 2009/ Accepted 14 May 2009

The endoplasmic reticulum (ER) is the major cellular compartment where folding and maturation of secretory and membrane proteins take place. When protein folding needs exceed the capacity of the ER, the unfolded protein response (UPR) pathway modulates gene expression and downregulates protein translation to restore homeostasis. Here, we report that the UPR downregulates the synthesis of rRNA by inactivation of the RNA polymerase I basal transcription factor RRN3/TIF-IA. Inhibition of rRNA synthesis does not appear to involve the well-characterized mTOR (mammalian target of rapamycin) pathway; instead, PERK-dependent phosphorylation of eIF2{alpha} plays a critical role in the inactivation of RRN3/TIF-IA. Downregulation of rRNA transcription occurs simultaneously or slightly prior to eIF2{alpha} phosphorylation-induced translation repression. Since rRNA is the most abundant RNA species, constituting ~90% of total cellular RNA, its downregulation exerts a significant impact on cell physiology. Our study demonstrates the first link between regulation of translation and rRNA synthesis with phosphorylation of eIF2{alpha}, suggesting that this pathway may be broadly utilized by stresses that activate eIF2{alpha} kinases in order to coordinately regulate translation and ribosome biogenesis during cellular stress.

* Corresponding author. Mailing address: Division of Biological Sciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Phone: (858) 822-3451. Fax: (858) 822-0317. E-mail: niwa{at}ucsd.edu

{triangledown} Published ahead of print on 26 May 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2009, p. 4295-4307, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00260-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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