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

TLR3, a major innate immune pattern recognition receptor of RNA viruses, triggers inflammatory response through the transcription factor NF-?B. However, a genome-wide understanding of the genes and mechanisms regulating TLR3-mediated NF-?B activation is incomplete. We herein report the results of a human genome-wide RNAi screen that identified 591 proteins regulating ...
TLR3-mediated NF-?B 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, IKK?, and IKK?. Furthermore, ATM was determined to coordinate the assembly of NEMO with TAK1, IKK?, and IKK? 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.
iScience
Date: Aug. 21, 2020
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