Digital signaling network drives the assembly of the AIM2-ASC inflammasome

Abstract

<p id="d7498232e184">The complexity of biological signaling pathways parallels the design of modern electronic circuits. The AIM2-ASC inflammasome is a filamentous signaling platform that plays an essential role in defense against foreign dsDNA arising from invading pathogens. Currently, the design principles of the AIM2-ASC “signaling circuit” remain poorly understood. Here, we found that the assembly of the AIM2-ASC inflammasome filters short dsDNA as noise at each signaling step. dsDNA induces hysteresis, and the assembly generates multistage, virtually infinite signal amplification. Moreover, an array of positive feedback loops reinforces the assembly. Together with a quantitative model of the assembly pathway, we demonstrate that an ultrasensitive digital circuit drives the assembly of the AIM2-ASC inflammasome on foreign dsDNA. </p><p class="first" id="d7498232e187">The AIM2-ASC inflammasome is a filamentous signaling platform essential for mounting host defense against cytoplasmic dsDNA arising not only from invading pathogens but also from damaged organelles. Currently, the design principles of its underlying signaling network remain poorly understood at the molecular level. We show here that longer dsDNA is more effective in inducing AIM2 assembly, its self-propagation, and downstream ASC polymerization. This observation is related to the increased probability of forming the base of AIM2 filaments, and indicates that the assembly discerns small dsDNA as noise at each signaling step. Filaments assembled by receptor AIM2, downstream ASC, and their joint complex all persist regardless of dsDNA, consequently generating sustained signal amplification and hysteresis. Furthermore, multiple positive feedback loops reinforce the assembly, as AIM2 and ASC filaments accelerate the assembly of nascent AIM2 with or without dsDNA. Together with a quantitative model of the assembly, our results indicate that an ultrasensitive digital circuit drives the assembly of the AIM2-ASC inflammasome. </p>