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

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 TNFalpha expression.
Mesh Terms:
14-3-3 Proteins, Adenosine, Animals, Arsenites, Binding Sites, Cell Line, Cercopithecus aethiops, DNA-Binding Proteins, Enzyme Activation, Humans, Immediate-Early Proteins, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Macrophages, Mice, Mutation, Protein Binding, Protein-Serine-Threonine Kinases, RNA Stability, RNA, Messenger, Regulatory Sequences, Ribonucleic Acid, Serine, Stress, Physiological, Tristetraprolin, Uridine, p38 Mitogen-Activated Protein Kinases
EMBO J.
Date: Mar. 24, 2004
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