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Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC.

Morrone SR, Matyszewski M, Yu X, Delannoy M, Egelman EH, Sohn J - Nat Commun (2015)

Bottom Line: The ability to oligomerize is critical for binding dsDNA, and in turn permits the size of dsDNA to regulate the assembly of the AIM2 polymers.The AIM2(PYD) oligomers define the filamentous structure, and the helical symmetry of the AIM2(PYD) filament is consistent with the filament assembled by the PYD of the downstream adaptor ASC.Our results suggest that the role of AIM2(PYD) is not autoinhibitory, but generating a structural template by coupling ligand binding and oligomerization is a key signal transduction mechanism in the AIM2 inflammasome.

View Article: PubMed Central - PubMed

Affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine Baltimore, Maryland 21205, USA.

ABSTRACT
AIM2 recognizes foreign dsDNA and assembles into the inflammasome, a filamentous supramolecular signalling platform required to launch innate immune responses. We show here that the pyrin domain of AIM2 (AIM2(PYD)) drives both filament formation and dsDNA binding. In addition, the dsDNA-binding domain of AIM2 also oligomerizes and assists in filament formation. The ability to oligomerize is critical for binding dsDNA, and in turn permits the size of dsDNA to regulate the assembly of the AIM2 polymers. The AIM2(PYD) oligomers define the filamentous structure, and the helical symmetry of the AIM2(PYD) filament is consistent with the filament assembled by the PYD of the downstream adaptor ASC. Our results suggest that the role of AIM2(PYD) is not autoinhibitory, but generating a structural template by coupling ligand binding and oligomerization is a key signal transduction mechanism in the AIM2 inflammasome.

No MeSH data available.


Related in: MedlinePlus

A model for the assembly of the AIM2 inflammasome.AIM2PYD is not auto-regulated. Depending on its cellular concentration, auto-assembly or dsDNA-mediated assembly will drive the initial filament formation. Importantly, basal AIM2 requires large dsDNA to generate energetically stable nucleoprotein complexes, because oligomerization is integral to dsDNA binding. The oligomerization of AIM2Hin is important for auto- or dsDNA-mediated filament assembly, but the construction of the filamentous architecture is dictated by AIM2PYD. The resulting AIM2 filaments then nucleate the assembly of the ASC filaments via corresponding helical architecture (ASCCARD is not shown in the filament for simplicity).
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f9: A model for the assembly of the AIM2 inflammasome.AIM2PYD is not auto-regulated. Depending on its cellular concentration, auto-assembly or dsDNA-mediated assembly will drive the initial filament formation. Importantly, basal AIM2 requires large dsDNA to generate energetically stable nucleoprotein complexes, because oligomerization is integral to dsDNA binding. The oligomerization of AIM2Hin is important for auto- or dsDNA-mediated filament assembly, but the construction of the filamentous architecture is dictated by AIM2PYD. The resulting AIM2 filaments then nucleate the assembly of the ASC filaments via corresponding helical architecture (ASCCARD is not shown in the filament for simplicity).

Mentions: We have presented here evidence supporting an oligomerization-driven activation mechanism for initiating the assembly of the AIM2 inflammasome in the absence of the currently prevailing autoinhibitory mechanism3233 (Fig. 9). For instance, the basal concentration of AIM2 is presumably sub-nanomolar under normal conditions, but is dramatically raised on pathogenic invasion (AIM2 is overexpressed by type-1 interferons by at least 200-fold)182039. Thus, in the absence of cytosolic dsDNA, we propose that AIM2 would fail to oligomerize and induce the polymerization of ASC, due to its low basal concentration. For instance, in physiologically relevant reaction conditions, AIM2 can assemble into a filament on dsDNA larger than 300 bp even at pico-molar concentrations, but it requires nearly 10,000-fold more AIM2 molecules to auto-assemble filaments without dsDNA (Figs 2 and 5, and Supplementary Fig. 2a). On the other hand, because oligomerization is coupled with dsDNA binding, individual AIM2 molecules are capable of finding one another even in the presence of excess dsDNA (Fig. 5). Thus, when foreign dsDNA invades, basal AIM2 would rapidly cluster into a seed filament necessary to nucleate the polymerization of ASC.


Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC.

Morrone SR, Matyszewski M, Yu X, Delannoy M, Egelman EH, Sohn J - Nat Commun (2015)

A model for the assembly of the AIM2 inflammasome.AIM2PYD is not auto-regulated. Depending on its cellular concentration, auto-assembly or dsDNA-mediated assembly will drive the initial filament formation. Importantly, basal AIM2 requires large dsDNA to generate energetically stable nucleoprotein complexes, because oligomerization is integral to dsDNA binding. The oligomerization of AIM2Hin is important for auto- or dsDNA-mediated filament assembly, but the construction of the filamentous architecture is dictated by AIM2PYD. The resulting AIM2 filaments then nucleate the assembly of the ASC filaments via corresponding helical architecture (ASCCARD is not shown in the filament for simplicity).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525163&req=5

f9: A model for the assembly of the AIM2 inflammasome.AIM2PYD is not auto-regulated. Depending on its cellular concentration, auto-assembly or dsDNA-mediated assembly will drive the initial filament formation. Importantly, basal AIM2 requires large dsDNA to generate energetically stable nucleoprotein complexes, because oligomerization is integral to dsDNA binding. The oligomerization of AIM2Hin is important for auto- or dsDNA-mediated filament assembly, but the construction of the filamentous architecture is dictated by AIM2PYD. The resulting AIM2 filaments then nucleate the assembly of the ASC filaments via corresponding helical architecture (ASCCARD is not shown in the filament for simplicity).
Mentions: We have presented here evidence supporting an oligomerization-driven activation mechanism for initiating the assembly of the AIM2 inflammasome in the absence of the currently prevailing autoinhibitory mechanism3233 (Fig. 9). For instance, the basal concentration of AIM2 is presumably sub-nanomolar under normal conditions, but is dramatically raised on pathogenic invasion (AIM2 is overexpressed by type-1 interferons by at least 200-fold)182039. Thus, in the absence of cytosolic dsDNA, we propose that AIM2 would fail to oligomerize and induce the polymerization of ASC, due to its low basal concentration. For instance, in physiologically relevant reaction conditions, AIM2 can assemble into a filament on dsDNA larger than 300 bp even at pico-molar concentrations, but it requires nearly 10,000-fold more AIM2 molecules to auto-assemble filaments without dsDNA (Figs 2 and 5, and Supplementary Fig. 2a). On the other hand, because oligomerization is coupled with dsDNA binding, individual AIM2 molecules are capable of finding one another even in the presence of excess dsDNA (Fig. 5). Thus, when foreign dsDNA invades, basal AIM2 would rapidly cluster into a seed filament necessary to nucleate the polymerization of ASC.

Bottom Line: The ability to oligomerize is critical for binding dsDNA, and in turn permits the size of dsDNA to regulate the assembly of the AIM2 polymers.The AIM2(PYD) oligomers define the filamentous structure, and the helical symmetry of the AIM2(PYD) filament is consistent with the filament assembled by the PYD of the downstream adaptor ASC.Our results suggest that the role of AIM2(PYD) is not autoinhibitory, but generating a structural template by coupling ligand binding and oligomerization is a key signal transduction mechanism in the AIM2 inflammasome.

View Article: PubMed Central - PubMed

Affiliation: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine Baltimore, Maryland 21205, USA.

ABSTRACT
AIM2 recognizes foreign dsDNA and assembles into the inflammasome, a filamentous supramolecular signalling platform required to launch innate immune responses. We show here that the pyrin domain of AIM2 (AIM2(PYD)) drives both filament formation and dsDNA binding. In addition, the dsDNA-binding domain of AIM2 also oligomerizes and assists in filament formation. The ability to oligomerize is critical for binding dsDNA, and in turn permits the size of dsDNA to regulate the assembly of the AIM2 polymers. The AIM2(PYD) oligomers define the filamentous structure, and the helical symmetry of the AIM2(PYD) filament is consistent with the filament assembled by the PYD of the downstream adaptor ASC. Our results suggest that the role of AIM2(PYD) is not autoinhibitory, but generating a structural template by coupling ligand binding and oligomerization is a key signal transduction mechanism in the AIM2 inflammasome.

No MeSH data available.


Related in: MedlinePlus