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.
Division of Rheumatology and Immunology, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA.
M
M
Piecyk
S
S
Wax
A R
AR
Beck
N
N
Kedersha
M
M
Gupta
B
B
Maritim
S
S
Chen
C
C
Gueydan
V
V
Kruys
M
M
Streuli
P
P
Anderson
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