FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression.
The Fas-activated serine/threonine phosphoprotein (FAST) is tethered to the outer mitochondrial membrane, where it interacts with BCL-X(L) (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.
Li
Wei
W
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA.
Simarro
Maria
M
Kedersha
Nancy
N
Anderson
Paul
P
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002457:Cell Extracts / Q000737:chemistry; D002458:Cell Fractionation; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013312:Stress, Physiological; D019014:fas Receptor / Q000378:metabolism*
D002457:Cell Extracts; D024101:Mitochondrial Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D019014:fas Receptor; C076751:TIAL1 protein, human; D017346:Protein Serine-Threonine Kinases