TIA-1 is a translational silencer that selectively regulates the expression of TNF-[alpha]

• Published in: The EMBO journal 2000-08, Vol.19 (15), p.4154
• Main Authors: Piecyk, Monica, Wax, Stephen, Andreas R.P. Beck, Kedersha, Nancy, Gupta, Mita, Maritim, Beatrice, Chen, Samantha, Gueydan, Cyril, Kruys, Veronique, Streuli, Michel, Anderson, Paul
• Format: Article
• Language: English
• ISSN: 0261-4189; 1460-2075

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-[alpha]) 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-[alpha] transcripts, macrophages lacking TIA-1 produce significantly more TNF-[alpha] protein than wild-type controls. The half-life of TNF-[alpha] 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-[alpha] 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 1[beta], granulocyte-macrophage colony-stimulating factor or interferon [gamma], 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.