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Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation

TLR3, a major innate immune pattern recognition receptor of RNA viruses, triggers inflammatory response through the transcription factor NF-κB. However, a genome-wide understanding of the genes and mechanisms regulating TLR3-mediated NF-κB activation is incomplete. We herein report the results of a...

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Detalles Bibliográficos
Autores principales: Unniyampurath, Unnikrishnan, Crisci, Angela, Krishnan, Manoj N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393402/
https://www.ncbi.nlm.nih.gov/pubmed/32731169
http://dx.doi.org/10.1016/j.isci.2020.101356
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author Unniyampurath, Unnikrishnan
Crisci, Angela
Krishnan, Manoj N.
author_facet Unniyampurath, Unnikrishnan
Crisci, Angela
Krishnan, Manoj N.
author_sort Unniyampurath, Unnikrishnan
collection PubMed
description TLR3, a major innate immune pattern recognition receptor of RNA viruses, triggers inflammatory response through the transcription factor NF-κB. However, a genome-wide understanding of the genes and mechanisms regulating TLR3-mediated NF-κB activation is incomplete. We herein report the results of a human genome-wide RNAi screen that identified 591 proteins regulating TLR3-mediated NF-κB response. Bioinformatics analysis revealed several signaling modules including linear ubiquitination assembly complex and mediator protein complex network as regulators of TLR3 signaling. We further characterized the kinase ATM as a previously unknown positive regulator of TLR3 signaling. TLR3 pathway stimulation induced ATM phosphorylation and promoted interaction of ATM with TAK1, NEMO, IKKα, and IKKβ. Furthermore, ATM was determined to coordinate the assembly of NEMO with TAK1, IKKα, and IKKβ during TLR3 signaling. This study provided a comprehensive understanding of TLR3-mediated inflammatory signaling regulation and established a role for ATM in innate immune response.
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spelling pubmed-73934022020-08-04 Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation Unniyampurath, Unnikrishnan Crisci, Angela Krishnan, Manoj N. iScience Article TLR3, a major innate immune pattern recognition receptor of RNA viruses, triggers inflammatory response through the transcription factor NF-κB. However, a genome-wide understanding of the genes and mechanisms regulating TLR3-mediated NF-κB activation is incomplete. We herein report the results of a human genome-wide RNAi screen that identified 591 proteins regulating TLR3-mediated NF-κB response. Bioinformatics analysis revealed several signaling modules including linear ubiquitination assembly complex and mediator protein complex network as regulators of TLR3 signaling. We further characterized the kinase ATM as a previously unknown positive regulator of TLR3 signaling. TLR3 pathway stimulation induced ATM phosphorylation and promoted interaction of ATM with TAK1, NEMO, IKKα, and IKKβ. Furthermore, ATM was determined to coordinate the assembly of NEMO with TAK1, IKKα, and IKKβ during TLR3 signaling. This study provided a comprehensive understanding of TLR3-mediated inflammatory signaling regulation and established a role for ATM in innate immune response. Elsevier 2020-07-10 /pmc/articles/PMC7393402/ /pubmed/32731169 http://dx.doi.org/10.1016/j.isci.2020.101356 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Unniyampurath, Unnikrishnan
Crisci, Angela
Krishnan, Manoj N.
Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation
title Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation
title_full Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation
title_fullStr Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation
title_full_unstemmed Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation
title_short Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation
title_sort loss of function genetic screen identifies atm kinase as a positive regulator of tlr3-mediated nf-κb activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393402/
https://www.ncbi.nlm.nih.gov/pubmed/32731169
http://dx.doi.org/10.1016/j.isci.2020.101356
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