Signaling Crosstalk Mechanisms That May Fine-Tune Pathogen-Responsive NFκB

Abstract

Precise control of inflammatory gene expression is critical for effective host defense without excessive tissue damage. The principal regulator of inflammatory gene expression is nuclear factor kappa B (NFκB), a transcription factor. Nuclear NFκB activity is controlled by IκB proteins, whose stimulus-responsive degradation and re-synthesis provide for transient or dynamic regulation. The IκB-NFκB signaling module receives input signals from a variety of pathogen sensors, such as toll-like receptors (TLRs). The molecular components and mechanisms of NFκB signaling are well-understood and have been reviewed elsewhere in detail. Here we review the molecular mechanisms that mediate cross-regulation of TLR-IκB-NFκB signal transduction by signaling pathways that do not activate NFκB themselves, such as interferon signaling pathways. We distinguish between potential regulatory crosstalk mechanisms that (i) occur proximal to TLRs and thus may have stimulus-specific effects, (ii) affect the core IκB-NFκB signaling module to modulate NFκB activation in response to several stimuli. We review some well-documented examples of molecular crosstalk mechanisms and indicate other potential mechanisms whose physiological roles require further study.

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© 2019 Adelaja and Hoffmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 15 September 2018; Accepted: 19 February 2019; Published: 02 July 2019. Author Contributions: AA conducted the literature review, prepared figures, and wrote the manuscript. AH provided supervision, outlined the scope, and edited the manuscript. This work was supported by Ruth L. Kirschstein National Research Service Award T32HL69766 and the Medical Scientist Training Program (NIH NIGMS training grant GM008042). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. For the purposes of clarity and brevity, we established a narrow focus for this review. As a result, we did not cite some pertinent contributions. We acknowledge Fay Lin for critical reading of the review.

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