AIM2 inflammasome activation and regulation: A structural perspective - PubMed (original) (raw)

Review

AIM2 inflammasome activation and regulation: A structural perspective

Bing Wang et al. J Struct Biol. 2017 Dec.

Abstract

Absent in melanoma 2 (AIM2) inflammasome is a multi-protein platform that recognizes aberrant cytoplasmic dsDNA and induces cytokine maturation, release and pyroptosis. It is composed of AIM2, apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1. Recent X-ray crystallographic and high resolution cryo-electron microscopic (cryo-EM) studies have revealed a series of structures in AIM2 inflammasome activation and regulation. One prominent feature common in multiple steps is the assembly of high-order structures, especially helical filaments nucleated by upstream molecules, rather than stoichiometric complexes. In this review, we track the AIM2 inflammasome activation process step by step, using high-resolution structures to illustrate the overall architecture of AIM2 inflammasome and its assembly and regulatory mechanisms.

Keywords: AIM2; ASC; CARD; Caspase-1; Helical filament; High-order assembly; INCA; Inflammasome; P202; PYD; Polymerization.

Copyright © 2017 Elsevier Inc. All rights reserved.

PubMed Disclaimer

Figures

Figure 1

Figure 1

(A) Domain organization of AIM2, ASC, caspase-1, p202, and INCA. Spheres, rectangles, and hexagons represent PYD, HIN, and CARD domains, respectively. (B) Crystal structure of AIM2HIN binds to a 19-bp dsDNA (PDB ID: 3RN5). AIM2HIN is colored in orange and DNA is in gray. (C) AIM2PYD filament structure reconstructed at ~ 5.0 Å. One protomer is colored in blue while the rest are in gray. (D) ASCPYD filament structure reconstructed at ~ 3.8 Å (PDB ID: 3J63). Two orthogonal views are shown. ASCPYD protomers are colored in three different shades of cyan. Arrowheads indicate ASCPYD C-termini. (E) Two orthogonal views of Casp1CARD filament reconstructed at ~ 4.8 Å (PDB ID: 5FNA). The filament is colored in a gray gradient with one protomer colored in pink. (F) Crystal structure of p202HIN1 in complex with a 20-bp dsDNA (PDB ID: 4L5R) with p202HIN1 colored in light blue and DNA in gray. The orientation of p202HIN1 is the same as AIM2HIN in (B). (G) Surface representation of p202HIN2 tetramer. Two protomers are colored in shades of salmon and the other two in gray. One protomer is also shown as a ribbon diagram.

Figure 2

Figure 2

A diagram of AIM2 inflammasome activation and regulation. Domains are represented in the same way as in Figure 1A. Step A: dsDNA binds to AIM2HIN. AIM2PYD is free to self-associate. Step B: AIM2 clusters on dsDNA. AIM2PYD forms filamentous structure. Step C: Filamentous AIM2PYD nucleated ASCPYD filament formation. Step D: Filamentous ASC nucleates filament formation of caspase-1. Step E: p202 blocks further access to dsDNA and separates bound AIM2. Step F: INCA caps caspase-1 filament, preventing further growth and activation.

Similar articles

Cited by

References

    1. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16:407–420. - PubMed
    1. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009;10:266–272. - PubMed
    1. Cridland JA, Curley EZ, Wykes MN, Schroder K, Sweet MJ, Roberts TL, Ragan MA, Kassahn KS, Stacey KJ. The mammalian PYHIN gene family: phylogeny, evolution and expression. BMC evolutionary biology. 2012;12:140. - PMC - PubMed
    1. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–513. - PMC - PubMed
    1. Ferrao R, Wu H. Helical assembly in the death domain (DD) superfamily. Curr Opin Struct Biol. 2012;22:241–247. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources