Abstract
Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1-driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd-deficient cells is caused by a synergistic effect of rapid caspase-1-driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1-dependent inflammatory disease.
Highlights
Inflammasomes are cytosolic signalling platforms assembled after the recognition of host- or pathogen-derived danger signals by cytosolic pattern recognition receptors, such as pyrin, AIM2, and members of the Nod like receptor (NLR) protein family (Broz & Dixit, 2016)
GSDMD is essential for lytic cell death after LPS-induced noncanonical inflammasome activation (Fig S1A), Gsdmd deficiency only delays cell lysis after engagement of canonical inflammasome receptors, such as AIM2 (Figs 1A and S1B–D), NLRC4, and NLRP3 (Figs 1A and S1B–D) (Kayagaki et al, 2015)
We tested a number of cell death inhibitors for their ability to block cell lysis in Gsdmd−/− immortalized BMDMs transfected with poly(dA:dT), an activator of the AIM2 inflammasome (Fig S2)
Summary
Inflammasomes are cytosolic signalling platforms assembled after the recognition of host- or pathogen-derived danger signals by cytosolic pattern recognition receptors, such as pyrin, AIM2, and members of the Nod like receptor (NLR) protein family (Broz & Dixit, 2016). Uncontrolled inflammasome activation by gain-of-function mutations in inflammasome receptors or in the context of sterile inflammatory disease has been linked to a number of hereditary and acquired inflammatory diseases, such as cryopyrin-associated periodic syndrome (Muckle–Wells syndrome), and gout, Alzheimer’s disease, and atherosclerosis (Masters et al, 2009). It is, of high interest to target and inhibit inflammasome assembly or downstream effector processes such as GSDMD pore formation and IL-1β release
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