Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.

NF-κB plays a vital role in cellular immune and inflammatory response, survival, and proliferation by regulating the transcription of various genes involved in these processes. To activate transcription, RelA (a prominent NF-κB family member) interacts with transcriptional co-activators like CREB-bi...

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Autores principales:	Sulakshana P Mukherjee, Marcelo Behar, Harry A Birnbaum, Alexander Hoffmann, Peter E Wright, Gourisankar Ghosh
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/dd6f87921bc640d0b792f168fa576437
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spelling	oai:doaj.org-article:dd6f87921bc640d0b792f168fa5764372021-11-18T05:37:51ZAnalysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.1544-91731545-788510.1371/journal.pbio.1001647https://doaj.org/article/dd6f87921bc640d0b792f168fa5764372013-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24019758/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885NF-κB plays a vital role in cellular immune and inflammatory response, survival, and proliferation by regulating the transcription of various genes involved in these processes. To activate transcription, RelA (a prominent NF-κB family member) interacts with transcriptional co-activators like CREB-binding protein (CBP) and its paralog p300 in addition to its cognate κB sites on the promoter/enhancer regions of DNA. The RelA:CBP/p300 complex is comprised of two components--first, DNA binding domain of RelA interacts with the KIX domain of CBP/p300, and second, the transcriptional activation domain (TAD) of RelA binds to the TAZ1 domain of CBP/p300. A phosphorylation event of a well-conserved RelA(Ser276) is prerequisite for the former interaction to occur and is considered a decisive factor for the overall RelA:CBP/p300 interaction. The role of the latter interaction in the transcription of RelA-activated genes remains unclear. Here we provide the solution structure of the latter component of the RelA:CBP complex by NMR spectroscopy. The structure reveals the folding of RelA-TA2 (a section of TAD) upon binding to TAZ1 through its well-conserved hydrophobic sites in a series of grooves on the TAZ1 surface. The structural analysis coupled with the mechanistic studies by mutational and isothermal calorimetric analyses allowed the design of RelA-mutants that selectively abrogated the two distinct components of the RelA:CBP/p300 interaction. Detailed studies of these RelA mutants using cell-based techniques, mathematical modeling, and genome-wide gene expression analysis showed that a major set of the RelA-activated genes, larger than previously believed, is affected by this interaction. We further show how the RelA:CBP/p300 interaction controls the nuclear response of NF-κB through the negative feedback loop of NF-κB pathway. Additionally, chromatin analyses of RelA target gene promoters showed constitutive recruitment of CBP/p300, thus indicating a possible role of CBP/p300 in recruitment of RelA to its target promoter sites.Sulakshana P MukherjeeMarcelo BeharHarry A BirnbaumAlexander HoffmannPeter E WrightGourisankar GhoshPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 11, Iss 9, p e1001647 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Sulakshana P Mukherjee Marcelo Behar Harry A Birnbaum Alexander Hoffmann Peter E Wright Gourisankar Ghosh Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.
description	NF-κB plays a vital role in cellular immune and inflammatory response, survival, and proliferation by regulating the transcription of various genes involved in these processes. To activate transcription, RelA (a prominent NF-κB family member) interacts with transcriptional co-activators like CREB-binding protein (CBP) and its paralog p300 in addition to its cognate κB sites on the promoter/enhancer regions of DNA. The RelA:CBP/p300 complex is comprised of two components--first, DNA binding domain of RelA interacts with the KIX domain of CBP/p300, and second, the transcriptional activation domain (TAD) of RelA binds to the TAZ1 domain of CBP/p300. A phosphorylation event of a well-conserved RelA(Ser276) is prerequisite for the former interaction to occur and is considered a decisive factor for the overall RelA:CBP/p300 interaction. The role of the latter interaction in the transcription of RelA-activated genes remains unclear. Here we provide the solution structure of the latter component of the RelA:CBP complex by NMR spectroscopy. The structure reveals the folding of RelA-TA2 (a section of TAD) upon binding to TAZ1 through its well-conserved hydrophobic sites in a series of grooves on the TAZ1 surface. The structural analysis coupled with the mechanistic studies by mutational and isothermal calorimetric analyses allowed the design of RelA-mutants that selectively abrogated the two distinct components of the RelA:CBP/p300 interaction. Detailed studies of these RelA mutants using cell-based techniques, mathematical modeling, and genome-wide gene expression analysis showed that a major set of the RelA-activated genes, larger than previously believed, is affected by this interaction. We further show how the RelA:CBP/p300 interaction controls the nuclear response of NF-κB through the negative feedback loop of NF-κB pathway. Additionally, chromatin analyses of RelA target gene promoters showed constitutive recruitment of CBP/p300, thus indicating a possible role of CBP/p300 in recruitment of RelA to its target promoter sites.
format	article
author	Sulakshana P Mukherjee Marcelo Behar Harry A Birnbaum Alexander Hoffmann Peter E Wright Gourisankar Ghosh
author_facet	Sulakshana P Mukherjee Marcelo Behar Harry A Birnbaum Alexander Hoffmann Peter E Wright Gourisankar Ghosh
author_sort	Sulakshana P Mukherjee
title	Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.
title_short	Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.
title_full	Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.
title_fullStr	Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.
title_full_unstemmed	Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.
title_sort	analysis of the rela:cbp/p300 interaction reveals its involvement in nf-κb-driven transcription.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/dd6f87921bc640d0b792f168fa576437
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Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF-κB-driven transcription.

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