MK2‐induced tristetraprolin: 14‐3‐3 complexes prevent stress granule association and ARE‐mRNA decay

G Stoecklin, T Stubbs, N Kedersha, S Wax… - The EMBO …, 2004 - embopress.org
G Stoecklin, T Stubbs, N Kedersha, S Wax, WFC Rigby, TK Blackwell, P Anderson
The EMBO journal, 2004embopress.org
Stress granules (SGs) are dynamic cytoplasmic foci at which stalled translation initiation
complexes accumulate in cells subjected to environmental stress. SG‐associated proteins
such as TIA‐1, TIAR and HuR bind to AU‐rich element (ARE)‐containing mRNAs and
control their translation and stability. Here we show that tristetraprolin (TTP), an ARE‐
binding protein that destabilizes ARE‐mRNAs, is recruited to SGs that are assembled in
response to FCCP‐induced energy deprivation, but not arsenite‐induced oxidative stress …
Stress granules (SGs) are dynamic cytoplasmic foci at which stalled translation initiation complexes accumulate in cells subjected to environmental stress. SG‐associated proteins such as TIA‐1, TIAR and HuR bind to AU‐rich element (ARE)‐containing mRNAs and control their translation and stability. Here we show that tristetraprolin (TTP), an ARE‐binding protein that destabilizes ARE‐mRNAs, is recruited to SGs that are assembled in response to FCCP‐induced energy deprivation, but not arsenite‐induced oxidative stress. Exclusion of TTP from arsenite‐induced SGs is a consequence of MAPKAP kinase‐2 (MK2)‐induced phosphorylation at serines 52 and 178, which promotes the assembly of TTP:14‐3‐3 complexes. 14‐3‐3 binding excludes TTP from SGs and inhibits TTP‐dependent degradation of ARE‐containing transcripts. In activated RAW 264.7 macrophages, endogenous TTP:14‐3‐3 complexes bind to ARE‐RNA. Our data reveal the mechanism by which the p38‐MAPK/MK2 kinase cascade inhibits TTP‐mediated degradation of ARE‐containing transcripts and thereby contributes to lipopolysaccharide‐induced TNFα expression.
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