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TIA‐1 is a translational silencer that selectively regulates the expression of TNF‐α
Author(s) -
Piecyk Monica,
Wax Stephen,
Beck Andreas R.P.,
Kedersha Nancy,
Gupta Mita,
Maritim Beatrice,
Chen Samantha,
Gueydan Cyril,
Kruys Veronique,
Streuli Michel,
Anderson Paul
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.15.4154
Subject(s) - biology , silencer , microbiology and biotechnology , translation (biology) , protein expression , messenger rna , genetics , gene , mechanical engineering , engineering , inlet
TIA‐1 and TIAR are related proteins that bind to an AU‐rich element (ARE) in the 3′ untranslated region of tumor necrosis factor alpha (TNF‐α) transcripts. To determine the functional significance of this interaction, we used homologous recombination to produce mutant mice lacking TIA‐1. Although lipopolysaccharide (LPS)‐stimulated macrophages derived from wild‐type and TIA‐1 −/− mice express similar amounts of TNF‐α transcripts, macrophages lacking TIA‐1 produce significantly more TNF‐α protein than wild‐type controls. The half‐life of TNF‐α transcripts is similar in wild‐type and TIA‐1 −/− macrophages, indicating that TIA‐1 does not regulate transcript stability. Rather, the absence of TIA‐1 significantly increases the proportion of TNF‐α transcripts that associate with polysomes, suggesting that TIA‐1 normally functions as a translational silencer. TIA‐1 does not appear to regulate the production of interleukin 1β, granulocyte–macrophage colony‐stimulating factor or interferon γ, indicating that its effects are, at least partially, transcript specific. Mice lacking TIA‐1 are hypersensitive to the toxic effects of LPS, indicating that this translational control pathway may regulate the organismal response to microbial stress.