Article
- The EMBO Journal (2004) 23, 1313 - 1324
- doi:10.1038/sj.emboj.7600163
Published online: 11 March 2004
Subject Categories:
MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay
Georg Stoecklin1, Tiffany Stubbs1, Nancy Kedersha1, Stephen Wax1, William FC Rigby2, T Keith Blackwell3 and Paul Anderson1
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Medicine, Dartmouth Medical School, Lebanon, NH, USA
- CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA, USA
Correspondence to:
Paul Anderson, Division of Rheumatology and Immunology, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA. Tel.: +1 617 525 1202; Fax: +1 617 525 1310; E-mail: panderson@rics.bwh.harvard.edu
Received 1 October 2003; Accepted 16 February 2004
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 TNF
expression.
Keywords:
- AU-rich element,
- MAPKAP kinase-2,
- mRNA turnover,
- TNF
, - TTP
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