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Vol. 16, Issue 12, 5819-5831, December 2005

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Stable Ribosome Binding to the Endoplasmic Reticulum Enables Compartment-specific Regulation of mRNA Translation

Samuel B. Stephens ^*, Rebecca D. Dodd ^*, Joseph W. Brewer , Patrick J. Lager , Jack D. Keene , and Christopher V. Nicchitta ^*

^* Department of Cell Biology, Duke University Medical Center, Durham, NC 27710; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710; and Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153

Submitted July 28, 2005; Accepted September 29, 2005
Monitoring Editor: Jeffrey Brodsky

In eukaryotic cells, protein synthesis is compartmentalized; mRNAs encoding secretory/membrane proteins are translated on endoplasmic reticulum (ER)-bound ribosomes, whereas mRNAs encoding cytosolic proteins are translated on free ribosomes. mRNA partitioning between the two compartments occurs via positive selection: free ribosomes engaged in the translation of signal sequence-encoding mRNAs are trafficked from the cytosol to the ER. After translation termination, ER-bound ribosomes are thought to dissociate, thereby completing a cycle of mRNA partitioning. At present, the physiological basis for termination-coupled ribosome release is unknown. To gain insight into this process, we examined ribosome and mRNA partitioning during the unfolded protein response, key elements of which include suppression of the initiation stage of protein synthesis and polyribosome breakdown. We report that unfolded protein response (UPR)-elicited polyribosome breakdown resulted in the continued association, rather than release, of ER-bound ribosomes. Under these conditions, mRNA translation in the cytosol was suppressed, whereas mRNA translation on the ER was sustained. Furthermore, mRNAs encoding key soluble stress proteins (XBP-1 and ATF-4) were translated primarily on ER-bound ribosomes. These studies demonstrate that ribosome release from the ER is termination independent and identify new and unexpected roles for the ER compartment in the translational response to induction of the unfolded protein response.

Abbreviations used: DTT, dithiothreitol; eIF2, eukaryotic initiation factor 2; ER, endoplasmic reticulum; PERK, RNA-activated protein kinase-like endoplasmic reticulum kinase; poly(A), polyadenylic acid; poly(I), polyinosinic acid; poly(U), polyuridylic acid; RNP, ribonuclear particle; SRP, signal recognition particle.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Christopher V. Nicchitta (c.nicchitta{at}cellbio.duke.edu).

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