RNA-destabilizing factor tristetraprolin negatively regulates NF-kappaB signaling.
Tristetraprolin (TTP) is a CCCH zinc finger-containing protein that destabilizes mRNA by binding to an AU-rich element. Mice deficient in TTP develop a severe inflammatory syndrome mainly because of overproduction of tumor necrosis factor alpha. We report here that TTP also negatively regulates NF-kappaB signaling at the transcriptional corepressor level, by which it may repress inflammatory gene transcription. TTP expression inhibited NF-kappaB-dependent transcription. However, overexpression of TTP did not affect reporter mRNA stability. Instead, TTP functioned as a corepressor of p65/NF-kappaB. In support of this concept, we found that TTP physically interacted with the p65 subunit of NF-kappaB and was also associated with HDAC1, -3, and -7 in vivo. Treatment with histone deacetylase inhibitors or small interfering RNA induced HDAC1 or HDAC3 knockdown completely or partly abolished the inhibitory activity of TTP on NF-kappaB reporter activation. Consistently, chromatin immunoprecipitation showed decreased recruitment of HDAC1 and increased recruitment of CREB-binding protein on the Mcp-1 promoter in TTP(-/-) cells compared with wild-type cells. Moreover, overexpression of TTP blocked CREB-binding protein-induced acetylation of p65/NF-kappaB. Taken together, these data suggest that TTP may also function in vivo as a modulator in suppressing the transcriptional activity of NF-kappaB.
Liang
Jian
J
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32816, USA.
Lei
Tianhua
T
Song
Yuting
Y
Yanes
Natalie
N
Qi
Yongfen
Y
Fu
Mingui
M
D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020871:RNA Stability / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D050882:CREB-Binding Protein; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D051816:Tristetraprolin; D000099186:Histone Deacetylase 3; C491768:Ccl2 protein, mouse; C498144:Rela protein, mouse; C497553:Zfp36 protein, mouse; C494364:Crebbp protein, mouse; C484389:Hdac1 protein, mouse