Dual Feedforward Loops Modulate Type I Interferon Responses and Induce Selective Gene Expression during TLR4...

Area of Science:

• Systems Biology
• Molecular Biology
• Immunology

Background:

• Type I coherent feedforward loops (C1-FFLs) are crucial regulatory motifs in biological systems.
• The role of C1-FFLs in shaping cell-to-cell heterogeneity in signaling pathways is not well understood.

Purpose of the Study:

• To investigate how C1-FFLs influence cell-to-cell variability in signaling molecule activation.
• To elucidate the distinct roles of OR-logic and AND-logic C1-FFLs in noise modulation.
• To understand the mechanisms underlying Toll-like receptor 4 (TLR4)-mediated type I interferon (IFN) responses.

Main Methods:

• Analysis of C1-FFL dynamics and their impact on signaling heterogeneity.
• Experimental investigation within the TLR4 signaling pathway.
• Development of a mathematical model incorporating dual C1-FFLs.

Main Results:

• C1-FFLs with OR logic act as noise reducers, while those with AND logic act as noise propagators.
• In TLR4 signaling, a MyD88-TRIF-mediated C1-FFL reduces TBK1 phosphorylation heterogeneity.
• Noisy TRIF activation leads to high IRF3 activation heterogeneity via a separate C1-FFL.
• Dual C1-FFLs differentially encode dynamics for TBK1 and IRF3 activation, with the MyD88-TBK1 axis controlling IFN-stimulated gene transcription specificity.

Conclusions:

• Dual C1-FFLs provide a mechanism for fine-tuning cell-to-cell heterogeneity in signaling pathways.
• The interplay between MyD88 and TRIF, mediated by dual C1-FFLs, dictates the specificity and dynamics of TLR4-induced type I IFN responses.