Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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14-3-3 Proteins / metabolism*
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Adenosine / genetics
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Animals
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Arsenites / pharmacology
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Binding Sites
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Cell Line
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Chlorocebus aethiops
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Activation
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Signaling System
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Macrophages / metabolism
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Mice
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Mutation / genetics
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Stability*
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism*
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Regulatory Sequences, Ribonucleic Acid / genetics*
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Serine / genetics
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Serine / metabolism
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Stress, Physiological
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Tristetraprolin
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Uridine / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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14-3-3 Proteins
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Arsenites
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DNA-Binding Proteins
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Immediate-Early Proteins
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Intracellular Signaling Peptides and Proteins
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RNA, Messenger
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Regulatory Sequences, Ribonucleic Acid
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Tristetraprolin
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ZFP36 protein, human
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Zfp36 protein, mouse
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Serine
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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Adenosine
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arsenite
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Uridine