4.5 Article

FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression

Journal

MOLECULAR AND CELLULAR BIOLOGY
Volume 24, Issue 24, Pages 10718-10732

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.24.10718-10732.2004

Keywords

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Funding

  1. NIAID NIH HHS [AI 33600, R01 AI050167, R56 AI033600, R01 AI033600, AI 50167] Funding Source: Medline
  2. NIAMS NIH HHS [R01 AR051472, AR 051472] Funding Source: Medline

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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.

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