TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha.
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.
Piecyk
M
M
Division of Rheumatology and Immunology, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA.
Wax
S
S
Beck
A R
AR
Kedersha
N
N
Gupta
M
M
Maritim
B
B
Chen
S
S
Gueydan
C
C
Kruys
V
V
Streuli
M
M
Anderson
P
P
D020413:3' Untranslated Regions; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation; D017737:Macrophages, Peritoneal / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D014176:Protein Biosynthesis; D011506:Proteins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000401:mortality; D000074019:T-Cell Intracellular Antigen-1; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D020413:3' Untranslated Regions; D016207:Cytokines; D008565:Membrane Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C499367:Tia1 protein, mouse; C489665:Tial1 protein, mouse; D014409:Tumor Necrosis Factor-alpha