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

Nat Commun. 2015 Jul 22:6:7827. doi: 10.1038/ncomms8827.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins / metabolism
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Escherichia coli
  • Immunity, Innate
  • Inflammasomes*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Maltose-Binding Proteins / metabolism
  • Microscopy, Electron
  • Molecular Sequence Data
  • Mutagenesis

Substances

  • AIM2 protein, human
  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Ifi202b protein, mouse
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • Maltose-Binding Proteins
  • PYCARD protein, human
  • DNA