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Molecular and Cellular Biology, December 2004, p. 10718-10732, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10718-10732.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

FAST Is a Survival Protein That Senses Mitochondrial Stress and Modulates TIA-1-Regulated Changes in Protein Expression

Wei Li, Maria Simarro, Nancy Kedersha, and Paul Anderson*

Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts

Received 24 May 2004/ Returned for modification 6 July 2004/ Accepted 15 September 2004

The Fas-activated serine/threonine phosphoprotein (FAST) is tethered to the outer mitochondrial membrane, where it interacts with BCL-XL (17). Here we show that RNA interference-mediated knockdown of endogenous FAST results in apoptosis, whereas overexpressed recombinant FAST inhibits Fas- and UV-induced apoptosis, indicating that FAST is a survival protein. The antiapoptotic effects of FAST are regulated by interactions with the translational silencer TIA-1: a FAST mutant lacking its TIA-1-binding domain does not inhibit apoptosis, and overexpressed recombinant TIA-1 inhibits the antiapoptotic effects of FAST. Because the antiapoptotic effects of FAST require ongoing protein synthesis, we hypothesized that FAST might function by preventing TIA-1-mediated silencing of mRNAs encoding inhibitors of apoptosis. Consistent with this hypothesis, FAST promotes the expression of cotransfected reporter proteins, a process that requires its TIA-1-binding domain and is inhibited by overexpressed recombinant TIA-1. More compellingly, recombinant FAST increases the expression of endogenous cIAP-1 and XIAP, but not GAPDH, in transfected HeLa cells. Because FAST is released from mitochondria in cells undergoing Fas- or UV-induced apoptosis, we propose that FAST serves as a sensor of mitochondrial stress that modulates a TIA-1-regulated posttranscriptional stress response program.

* Corresponding author. Mailing address: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115. Phone: (617) 525-1202. Fax: (617) 525-1310. E-mail: panderson{at}rics.bwh.harvard.edu.

Molecular and Cellular Biology, December 2004, p. 10718-10732, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10718-10732.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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