Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation
Summary: 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 resu...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-08-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220305435 |
| _version_ | 1818456869261279232 |
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| author | Unnikrishnan Unniyampurath Angela Crisci Manoj N. Krishnan |
| author_facet | Unnikrishnan Unniyampurath Angela Crisci Manoj N. Krishnan |
| author_sort | Unnikrishnan Unniyampurath |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-14T22:33:31Z |
| format | Article |
| id | doaj.art-4ba19553beaa4fe5930f587f0b0f6063 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-14T22:33:31Z |
| publishDate | 2020-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-4ba19553beaa4fe5930f587f0b0f60632022-12-21T22:45:12ZengElsevieriScience2589-00422020-08-01238101356Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB ActivationUnnikrishnan Unniyampurath0Angela Crisci1Manoj N. Krishnan2Program on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore, SingaporeProgram on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore, SingaporeProgram on Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore, Singapore; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220305435Biological SciencesImmunologyCell Biology |
| spellingShingle | Unnikrishnan Unniyampurath Angela Crisci Manoj N. Krishnan Loss of Function Genetic Screen Identifies ATM Kinase as a Positive Regulator of TLR3-Mediated NF-κB Activation iScience Biological Sciences Immunology Cell Biology |
| 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 | Biological Sciences Immunology Cell Biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220305435 |
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