Cytosolic DNA detection by the inflammasome and beyond — ASN Events

Cytosolic DNA detection by the inflammasome and beyond (#S-32)

Veit Hornung 1
  1. University Hospital, University of Bonn, Bonn, Germany

Inflammasomes are large multi-protein complexes that trigger the activation of so called inflammatory caspases, most importantly caspase-1. Upon activation, caspase-1 cleaves various substrates, including the pro-inflammatory cytokines IL-1β and IL-18, which are rendered active upon proteolytic maturation. Beyond these members of the IL-1 family, multiple additional caspase-1 targets have been identified, yet the physiological role of these cleavage events remains to be elucidated. Moreover, caspase-1 activation leads to a certain type of cell death, named pyroptosis, that can also trigger inflammation in trans. Various sensor proteins have been identified that can trigger the formation of inflammasome platforms. These inflammasome-forming PRRs, except for the DNA sensor AIM2, belong to the Nod-like receptor (NLR) family. NLRs are cytosolic PRRs with a tripartite domain architecture comprising of C-terminal leucine-rich repeats (LRRs) that are thought to sense microbial molecules or endogenous stress mediators; a central NACHT nucleoside triphosphatase domain that mediates NLR oligomerization and formation of the core structure of the inflammasome; and an N-terminal effector domain required for signal transduction. AIM2 is an exception to this rule, as it contains a unique C-terminal ligand binding domain, the HIN200 domain. While AIM2 plays a non-redundant role in sensing the presence of cytosolic DNA leading to ASC-dependent inflammasome activation, other cytosolic DNA sensing mechanisms have been identified that are required to drive pro-inflammatory gene expression. Among these, the recently identified cGAS/STING axis plays the predominant role. In this talk an update is given on our recent progress on the characterization of cytosolic DNA sensing pathways and their interconnection in the context of infectious and sterile inflammatory conditions.