Unified Polymerization Mechanism for the Assembly of ASC-dependent Inflammasomes

By A. Lu, V. Magupalli, J. Ruan, Q. Yin, Maninjay K. Atianand, M. Vos, Gunnar F. Schröder, Katherine A. Fitzgerald, Hao Wu, Edward H. Egelman. Cell, 2014

1,249 citations recorded by the source corpus.

SUMMARY Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrindomain (PYD) interactions between sensors and ASC, and caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which in turn cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1 leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryo-EM structure of ASCPYD filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/94939d30f0dc4bbcd7ead2711821f2924dfa40c7

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In Immunology

1. T. Kanneganti
2. M. Lamkanfi
3. V. Dixit
4. Jeffery L. Dangl
5. A. Grebe
6. E. Latz
7. F. Sutterwala
8. R. Vance

In Molecular Biology

1. T. Kanneganti
2. M. Lamkanfi
3. C. Brangwynne
4. S. Man
5. Rohit V. Pappu
6. V. Dixit
7. D. Sharma
8. Peter Tompa

Citations in the corpus

• Regulation of inflammasome activation (2015, background): “Cryo-electron microscopy analysis revealed that ASC and caspase-1 form filamentous structures following nucleation initiated by AIM2 or NLRP3 (169).”
• Initiation and perpetuation of NLRP3 inflammasome activation and assembly (2015, methodology): “Poeck H, et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production.”
• Mechanisms and functions of inflammasomes. (2014, background): “AIM2 and Nlrp3 nucleate ASC fibers through their PYD domains (Cai et al., 2014; Lu et al., 2014).”
• Intracellular innate immune surveillance devices in plants and animals (2016, background): “Interestingly, the pyrin domain of NLRP3 is also believed to propagate signaling by nucleating the oligomerization of ASC into polymerized filaments that coalesce into massive intracellular “specks” (34).”
• Human Monocytes Engage an Alternative Inflammasome Pathway. (2016, neutral): “Activated inflammasome sensor proteins have been shown to seed the prion-like assembly of the inflammasome adaptor ASC into filamentous, high-molecular-weight complexes (Cai et al., 2014; Lu et al., 2014), for which the term pyroptosome has originally been coined (Fernandes-Alnemri et al.”