State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China.
State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China.
Cell Metab. 2021 Feb 2;33(2):424-436.e10. doi: 10.1016/j.cmet.2020.11.018. Epub 2020 Dec 11.
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.
半胱天冬酶-4 是细胞质细菌脂多糖 (LPS) 的细胞内传感器，是感染引发细胞焦亡的基础。目前尚不清楚半胱天冬酶-4 是否以及如何检测宿主来源的因子来触发细胞焦亡。在这里，我们表明线粒体通透性转换 (MPT) 通过促进一种被称为凋亡相关因子-1 细胞焦亡体的蛋白质复合物的组装来激活半胱天冬酶-4，从而促进易化细胞焦亡的执行。MPT 可被胆汁酸、钙超载或腺嘌呤核苷酸转位酶 1 (ANT1) 激活剂诱导，触发由凋亡相关因子-1 和半胱天冬酶-4 组成的细胞焦亡体的组装，其比例为 7:2。与 LPS 连接时半胱天冬酶-4 对 gasdermin D (GSDMD) 的直接切割不同，在凋亡相关因子-1 细胞焦亡体中激活的半胱天冬酶-4 继续切割半胱天冬酶-3，从而切割 GSDME 以诱导细胞焦亡。半胱天冬酶-4 引发和 GSDME 执行的细胞焦亡是胆汁淤积性肝衰竭的基础。这些发现确定了凋亡相关因子-1 细胞焦亡体是细胞感知 MPT 信号的关键机制，可能有助于理解细胞在无菌条件下如何执行内在细胞焦亡。
