Figure 8

Involvement of DED proteins in the inflammasome. (a) Full activation of the inflammasomes requires a two-step process. Firstly, a priming signal is induced by a PAMP (such as LPS) activating a transcriptional cascade resulting in the de novo synthesis of inflammasome components such as NLRP3 and pro-IL-1β.¹³⁹ Of note, subsequent work has shown that this is not always the case, as TLR-mediated priming of the NLRP3 inflammasome does not always require transcriptional upregulation of NLRP3.^{209, 210} (b) Assembly of the inflammasome components NLRP3, ASC and pro-caspase-1 occurs following a second signal. This can be any one of numerous different stimuli, for example, ATP activation of the P2X7 receptor, bacterial toxins, nigericin and silica.^{211, 212, 213} A subsequent efflux of potassium from the cell permits the components to form a functional canonical NLRP3 inflammasome where pro-caspase-1 is cleaved into its active form.²¹⁴ Catalytically active caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature forms, which are then released from the cell.²¹¹ (c) Fungi and mycobacterium activate the β-glucan receptor dectin-1 resulting in the phosphorylation of cytoplasmic domain allowing the recruitment of SYK kinase.²¹⁵ This elicits the formation of the non-canonical caspase-8 inflammasome, consisting of CARD9, BCL-10, MALT1, ASC and caspase-8. In this complex, active caspase-8 cleaves pro-IL-1β into its mature form which is released from the cell.²¹⁶ (d) IL-1β and IL-18 can be processed directly by caspase-8 in an ASC-independent manner following ligation of members of the TNF receptor family, such as CD95, although the mechanism for this remains unclear.¹⁴⁶ (e) The Ripoptosome forms upon loss of IAPs and can lead to activation of caspase-8, which can potentially cleave IL-1β directly or indirectly via caspase-1.^{150, 217}