Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Matyszewski M

PROVIDER: S-EPMC5834677 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Matyszewski Mariusz M Morrone Seamus R SR Sohn Jungsan J

Proceedings of the National Academy of Sciences of the United States of America 20180212 9

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 proba ...[more]

PMID: 29440442

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Project description:BACKGROUND:AIM2 binds dsDNA and associates with ASC through their PYDs to form an inflammasome. RESULTS:The AIM2 PYD structure illustrates distinct charge distribution and a unique hydrophobic patch. CONCLUSION:The AIM2 PYD may bind the ASC PYD and the AIM2 HIN domain through overlapping surface. SIGNIFICANCE:These findings provide insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. Absent in melanoma 2 (AIM2) is a cytosolic double-stranded (dsDNA) sensor essential for innate immune responses against DNA viruses and bacteria such as Francisella and Listeria. Upon dsDNA engagement, the AIM2 amino-terminal pyrin domain (PYD) is responsible for downstream signaling to the adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) through homotypic PYD-PYD interactions and the assembly of an inflammasome. Toward a better understanding of the AIM2 signaling mechanism, we determined the crystal structure of the human AIM2 PYD. The structure reveals a death domain fold with a short ?3 helix that is buttressed by a highly conserved lysine residue at the ?2 helix, which may stabilize the ?3 helix for potential interaction with partner domains. The surface of the AIM2 PYD exhibits distinct charge distribution with highly acidic ?1-?2 helices and highly basic ?5-?6 helices. A prominent solvent-exposed hydrophobic patch formed by residues Phe-27 and Phe-28 at the ?2 helix resembles a similar surface involved in the death effector domain homotypic interactions. Docking studies suggest that the AIM2 PYD may bind the AIM2 hematopoietic interferon-inducible nuclear (HIN) domain or ASC PYD using overlapping surface near the ?2 helix. This may ensure that AIM2 interacts with the downstream adapter ASC only upon release of the autoinhibition by the dsDNA ligand. Our work thus unveils novel structural features of the AIM2 PYD and provides insights into the potential mechanisms of the PYD-HIN and PYD-PYD interactions important for AIM2 autoinhibition and inflammasome assembly.

Dataset Information

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

Publications

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

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