AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC

Abstract

Inflammasomes are protein complexes assembled upon recognition of infection or cell damage signals, and serve as platforms for clustering and activation of procaspase-1. Oligomerisation of initiating proteins such as AIM2 (absent in melanoma-2) and NLRP3 (NOD-like receptor family, pyrin domain-containing-3) recruits procaspase-1 via the inflammasome adapter molecule ASC (apoptosis-associated speck-like protein containing a CARD). Active caspase-1 is responsible for rapid lytic cell death termed pyroptosis. Here we show that AIM2 and NLRP3 inflammasomes activate caspase-8 and -1, leading to both apoptotic and pyroptotic cell death. The AIM2 inflammasome is activated by cytosolic DNA. The balance between pyroptosis and apoptosis depended upon the amount of DNA, with apoptosis seen at lower transfected DNA concentrations. Pyroptosis had a higher threshold for activation, and dominated at high DNA concentrations because it happens more rapidly. Gene knockdown showed caspase-8 to be the apical caspase in the AIM2-and NLRP3-dependent apoptotic pathways, with little or no requirement for caspase-9. Procaspase-8 localised to ASC inflammasome 'specks' in cells, and bound directly to the pyrin domain of ASC. Thus caspase-8 is an integral part of the inflammasome, and this extends the relevance of the inflammasome to cell types that do not express caspase-1.

dsDNA ASCs for caspase 8-mediated apoptosis

“…epithelial tumor cells. This novel finding by Sagulenko et al 6 considerably changes our present view and understanding of which form of cell death has to be considered 'default' and 'backup', and which one is 'good' and beneficial for the host. Apparently, it is all a matter of the appropriate context.…”

“…A recent study of Sagulenko et al 6 in Cell Death and Differentiation now shows a yet different aspect of inflammasome-mediated cell death induction in macrophages. In the absence of caspase 1, activation of AIM2 by cytoplasmic dsDNA, or NLRP3 by the bacterial toxin nigericin leads to an ASC-mediated recruitment of caspase 8, and subsequent induction of apoptotic cell death, rather than pyroptosis (Figure 1).…”

Another twist in the on and off affair between cell suicide and inflammation

“…18 Cytoplasmic DNA triggered the AIM2 inflammasome to activate caspase 8 and caspase 1, leading to cell death with features of both apoptosis (such as activation of caspase 3 and caspase-activated DNAse (CAD)-mediated DNA laddering) as well as pyroptosis (such as rapid loss of plasma membrane integrity and release of IL-1b). 17 They found that lower concentrations of DNA led to pure apoptosis, whereas higher amounts caused pyroptosis as well. Once pyroptosis was triggered, it proceeded much more rapidly than apoptosis.…”

“…When higher levels of DNA are present (right panel), AIM2 and ASC form an inflammasome much more rapidly, and it activates caspase 1 that processes pro-IL-1b and causes cell death characteristic of pyroptosis. One of the surprising findings of Sagulenko et al 17 was that ASC can not only bind with procaspase 1 via their CARDs, but can also bind to procaspase 8 via pyrin-DED interactions responsible for Fas-induced apoptosis, 7,8 which suggested that caspase 1 was only involved in immune responses, and not in cell death. 9 This led to a new paradigm that there were two families of caspases: those involved in apoptosis (caspases 2, 3, 6, 7, 8, 9 and 10) and those involved in cytokine activation (caspases 1, 4, 5 and 11).…”

“…15,16 A paper in this edition of Cell Death and Differentiation advances the story even further by showing that the AIM2 and NLRP3 inflammasomes can trigger ASC to activate not only pyroptotic (IL-1b releasing) death pathways, but also an apoptotic pathway, and more surprisingly, caspase 8 is involved in both. 17 Sagulenko et al 17 looked at bone marrow-derived macrophages from normal and gene-deleted mice, and studied their responses to calf thymus or synthetic polydA:polydT DNA that had been electroporated across the plasma membrane. This treatment causes most wild-type macrophages to die within an hour.…”