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J. Biol. Chem., Vol. 282, Issue 41, 30070-30077, October 12, 2007

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T-cell Intracellular Antigen-1 (TIA-1)-induced Translational Silencing Promotes the Decay of Selected mRNAs^*

Satoshi Yamasaki, Georg Stoecklin, Nancy Kedersha, Maria Simarro, and Paul Anderson, Supported by National Institutes of Health Grants AI033600 and AI065858¹

From the Harvard Medical School, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115 and German Cancer Research Center, 69120 Heidelberg, Germany

Gene array analysis revealed that a subset of mRNAs overexpressed in macrophages lacking the destabilizing factor TTP are also overexpressed in macrophages lacking the translational silencer TIA-1. We confirmed that a representative transcript, apobec-1, is significantly stabilized in cells lacking TIA-1. Tethering TIA-1 to a reporter transcript also promotes mRNA decay, suggesting that TIA-1-mediated translational silencing can render mRNA susceptible to the decay machinery. TIA-1-mediated decay is inhibited by small interfering RNAs targeting components of either the 5'-3' (e.g. DCP2) or the 3'-5' (e.g. exosome component Rrp46) decay pathways, suggesting that TIA-1 renders mRNA susceptible to both major decay pathways. TIA-1-mediated decay is inhibited by cycloheximide and emetine, drugs that stabilize polysomes, but is unaffected by puromycin, a drug that disassembles polysomes. These results suggest that TIA-1-induced polysome disassembly is required for enhanced mRNA decay and that TIA-1-induced translational silencing promotes the decay of selected mRNAs.

Received for publication, July 30, 2007 , and in revised form, August 20, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Smith 652, One Jimmy Fund Way, Boston, MA 02115. Tel.: 617-525-1202; Fax: 617-525-1310; E-mail: panderson{at}rics.bwh.harvard.edu.

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