Caspase-4 is an intracellular sensor for cytosolic bacterial lipopolysaccharide (LPS) and underlies infection-elicited pyroptosis. It is unclear whether and how caspase-4 detects host-derived factors to trigger pyroptosis. Here we show that mitochondrial permeability transition (MPT) activates caspase-4 by promoting the assembly of a protein complex, which we term the Apaf-1 pyroptosome, for the execution of facilitated pyroptosis. MPT, when induced by bile acids, calcium overload, or an adenine nucleotide translocator 1 (ANT1) activator, triggers assembly of the pyroptosome comprised of Apaf-1 and caspase-4 with a stoichiometry ratio of 7:2. Unlike the direct cleavage of gasdermin D (GSDMD) by caspase-4 upon LPS ligation, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby GSDME to induce pyroptosis. Caspase-4-initiated and GSDME-executed pyroptosis underlies cholestatic liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed light on understanding how cells execute intrinsic pyroptosis under sterile conditions.

Caspase-4 是细胞溶质细菌脂多糖 (LPS) 的细胞内传感器，是感染引起的细胞焦亡的基础。目前尚不清楚 caspase-4 是否以及如何检测宿主衍生因子以触发细胞焦亡。在这里，我们表明线粒体通透性转变 (MPT) 通过促进蛋白质复合物的组装来激活 caspase-4，我们将其称为Apaf-1焦亡体，用于执行促进焦亡。MPT，当由胆汁酸、钙超载或腺嘌呤核苷酸转运蛋白 1 (ANT1) 激活剂诱导时，会触发由 Apaf-1 和 caspase-4 组成的焦糖体组装，化学计量比为 7:2。与 LPS 连接时 caspase-4 直接裂解 gasdermin D (GSDMD) 不同，在 Apaf-1 焦亡体中激活的 caspase-4 继续裂解 caspase-3，从而 GSDME 诱导焦亡。Caspase-4 启动和 GSDME 执行的细胞焦亡是胆汁淤积性肝衰竭的基础。这些发现将 Apaf-1 焦亡体确定为细胞感知 MPT 信号的关键机制，并可能阐明细胞如何在无菌条件下执行内在焦亡。