Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine Processing

Abstract

Summary Activation of the cysteine protease Caspase-1 is a key event in the innate immune response to infections. Synthesized as a pro-protein, Caspase-1 undergoes autoproteolysis within multi-protein complexes called inflammasomes. Activated Caspase-1 is required for proteolytic processing and release of the cytokines interleukin-1β and interleukin-18, and can also cause rapid macrophage cell death. We show that macrophage cell death and cytokine maturation in response to infection with diverse bacterial pathogens can be separated genetically and that two distinct inflammasome complexes mediate these events. Inflammasomes containing the signaling adaptor Asc form a single large ‘focus’ in which Caspase-1 undergoes autoproteolysis and processes IL-1β/IL-18. In contrast, Asc-independent inflammasomes activate Caspase-1 without autoproteolysis and do not form any large structures in the cytosol. Caspase-1 mutants unable to undergo autoproteolysis promoted rapid cell death, but processed IL-1β/18 inefficiently. Our results suggest the formation of spatially and functionally distinct inflammasomes complexes in response to bacterial pathogens.

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Double asterisk murine caspase-11 is orthologous to human caspase-4/-5. DED death effector domain, CARD caspase recruitment domain activated in this complex and subsequently cleaves the proforms of the inflammatory cytokines IL-1b/IL-18 to yield their active forms (Broz et al 2010;Thornberry et al 1992). The activated inflammasome also induces pyroptosis, a type of cell death that contributes to the removal of intracellular pathogens (Miao et al 2010).…”

Burn the house, save the day: pyroptosis in pathogen restriction

“…This cleavage event may be associated with stabilisation of the active site, as reported for initiator apoptotic caspases [15]. In contrast, self-processing between the large and the small subunits appeared dispensable for the initiation of pyroptosis, as wild-type and uncleavable mutants of caspase-1 were equally able to trigger pyroptosis in murine macrophages [14]. Pyroptosis execution does however absolutely require the catalytic activity of caspase-1 [5,14].…”

“…In contrast, self-processing between the large and the small subunits appeared dispensable for the initiation of pyroptosis, as wild-type and uncleavable mutants of caspase-1 were equally able to trigger pyroptosis in murine macrophages [14]. Pyroptosis execution does however absolutely require the catalytic activity of caspase-1 [5,14]. Caspase-1 is also cleaved in the linker between the CARD domain and the catalytic domain, but the outcome of this cleavage event remains unclear.…”

“…ASC acts as a signal adaptor that, upon binding to the sensor protein, recruits pro-caspase-1 to the complex. Procaspase-1 clustering within the inflammasome complex enables its activation through homodimerisation, an essential and probably sufficient step for the acquisition of enzymatic activity, which may be further influenced by self-cleavage [8,13,14]. Self-processing occurs between the large and the small subunit of caspase-1, and appears to be mandatory for caspase-1-directed maturation of the inflammasome target cytokines, IL-1β and IL-18.…”

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

“…Interestingly, ASC speck also appears upon the activation of NLRC4. While pyroptosis due to the activation of CARDcontaining receptors is not dependent on ASC [7,53,54], IL-1β maturation is strongly enhanced in the presence of ASC [53,55] (Fig. 5).…”