期刊
EMBO JOURNAL
卷 23, 期 6, 页码 1313-1324出版社
WILEY-BLACKWELL
DOI: 10.1038/sj.emboj.7600163
关键词
AU-rich element; MAPKAP kinase-2; mRNA turnover; TNF alpha; TTP
资金
- NCI NIH HHS [CA-84418, R01 CA084418] Funding Source: Medline
- NIAID NIH HHS [AI-50167, AI-33600, R01 AI050167, R01 AI033600, R56 AI033600] Funding Source: Medline
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.
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