TY - JOUR
T1 - Digital signaling network drives the assembly of the AIM2- ASC inflammasome
AU - Matyszewski, Mariusz
AU - Morrone, Seamus R.
AU - Sohn, Jungsan
N1 - Funding Information:
This work was supported by Jerome L. Greene Foundation and American Cancer Society Research Scholars Grant DMC- RG-15-224 (to J.S.).
Funding Information:
ACKNOWLEDGMENTS. This work was supported by Jerome L. Greene Foundation and American Cancer Society Research Scholars Grant DMC-RG-15-224 (to J.S.).
PY - 2018/2/27
Y1 - 2018/2/27
N2 - 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.
AB - 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.
KW - Digital circuit
KW - Inflammasome
KW - Innate immunity
KW - Signaling network
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U2 - 10.1073/pnas.1712860115
DO - 10.1073/pnas.1712860115
M3 - Article
C2 - 29440442
AN - SCOPUS:85042733608
SN - 0027-8424
VL - 115
SP - E1963-E1972
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -