Mechanism of caspase activation and execution of cell death. Caspases
trigger activation of apoptosis, a noninflammatory form of cell death. In
extrinsic apoptosis, death receptor activation facilitates recruitment of FADD
and caspase-8 to form the death-inducing signaling complex (DISC). Activated
caspase-8 in the DISC further processes executioner caspases (caspase-3, -7) to
engage apoptosis. In intrinsic apoptosis, intracellular stress stimuli induce
mitochondrial outer membrane permeabilization (MOMP). This leads to the release
of cytochrome c into the cytosol. Binding of cytochrome
c to APAF1 triggers assembly of the apoptosome complex,
which facilitates activation of caspase-9. This in turn promotes activation of
caspase-3 and -7 to execute apoptosis. Complex-I assembly is initiated by TNF
binding to TNFR on the membrane. This promotes prosurvival signaling via
receptor-interacting serine/threonine protein kinase 1 (RIPK1), TAK-TAB, and
NEMO proteins. Loss of RIPK1 ubiquitination promotes formation of the
intracellular ripoptosome complex. Inactivation of the catalytic activity of
caspase-8 in the ripoptosome complex induces RIPK1-RIPK3 association and
phosphorylation of MLKL to form pores on the membrane and engage necroptosis.
ZBP1 also activates necroptosis via RIPK3. Activation of inflammatory caspases
induces pyroptosis. Inflammasome assembly activates caspase-1 enzymatic
function. ASC in the inflammasome complex recruits caspase-1. Some
inflammasome-forming innate immune receptors recruit caspase-1 without the
involvement of an ASC protein. ZBP1 activates the NLRP3 inflammasome in response
to influenza infection. LPS binds to caspase-11 (or human caspase-4/-5) and
triggers its activation through oligomerization and cleavage. Activation of
caspase-1 and -11 proteolytically processes gasdermin D (GSDMD) to release the
N-terminal domain, which forms pores on the membrane to further induce
pyroptosis. Caspase-1 also cleaves pro-IL-1β and pro-IL-18 into
IL-1β and IL-18, which are released through GSDMD pores.
Caspase-3-mediated gasdermin E (GSDME) cleavage also drives pyroptosis.