TAILIEUCHUNG - Báo cáo Y học: Transcriptional activity of interferon regulatory factor (IRF)-3 depends on multiple protein–protein interactions

Virus infection results in the activation of a set of cellular genes involved in host antiviral defense. IRF-3 has been identifiedas a critical transcription factor in this process. The activationmechanismof IRF-3 is not fully elucidated,yet it involves a conformational change triggered by the virus-dependent phosphorylation of its C-terminus. This con-formational change leads to nuclear accumulation,DNA binding and transcriptional transactivation. | Eur. J. Biochem. 269 6142-6151 2002 FEBS 2002 doi Transcriptional activity of interferon regulatory factor IRF -3 depends on multiple protein-protein interactions Hongmei Yang1 Charles H. Lin2 Gang Ma1 Melissa Orr1 Michael O. Baffi1 and Marc G. Wathelet1 1 Department of Molecular and Cellular Physiology University of Cincinnati College of Medicine Cincinnati department of Molecular and Cellular Biology Harvard University Cambridge MA Virus infection results in the activation of a set of cellular genes involved in host antiviral defense. IRF-3 has been identified as a critical transcription factor in this process. The activation mechanism of IRF-3 is not fully elucidated yet it involves a conformational change triggered by the virusdependent phosphorylation of its C-terminus. This conformational change leads to nuclear accumulation DNA binding and transcriptional transactivation. Here we show that two distinct sets of Ser Thr residues of IRF-3 on phosphorylation synergize ftmcfionally to adiieve maximal activation. Remarkably we find dad aciivatd IRF-3 Sr IcS transcriptional activity but activates transcription entirely through the recruitment of the p300 CBP coactivators. Moreover we show that two tepnrate domains of RRFd interact with several distinct regions of p300 CBP. Interference with any of these interactions leads to a complete loss of transcriptional activity suggesting that a bivalent interaction is essential for coactivator recruitment by IRF-3. Keywords interferon IRF-3 coactivator virus transcription. Vertebrates respond to infections by first triggering the innate arm of the immune system upon recogniiing generic microbial products uich as ii popolysaec-haiides for Gramnegative bacteria or dsRNA for vinKes 11 2 . A uumbel of cytokines inuludmg iniffierons FFNs tumor nocrosis factors and several chemokines and interleukins are produced early upon infection. They signal to the organism the presence of the infection and .

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