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研究发现新的细胞焦亡途径
作者:小柯机器人 发布时间:2020/12/14 15:45:37

中国药科大学郝海平和曹丽娟团队合作揭示Apaf-1体感知线粒体通透性转变机制。该研究于2020年12月11日发表于《细胞-代谢》杂志。

他们显示线粒体通透性转变(MPT)通过促进蛋白质复合物的装配来激活caspase-4,他们将其称为Apaf-1焦王小体,以促进细胞凋亡。当由胆汁酸、钙超载或腺嘌呤核苷酸转运子1(ANT1)激活剂诱导时,MPT触发由Apaf-1和caspase-4组成的焦亡小体的组装,化学计量比为7:2。 脂多糖(LPS)连接后,胱天蛋白酶D(GSDMD)被caspase-4直接切割,与在Apaf-1焦小体中活化的caspase-4继续切割caspase-3并由此GSDME诱导细胞焦亡不同。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焦亡小体鉴定为细胞检测MPT信号的关键机制,并可能有助于了解细胞在无菌条件下如何执行固有的细胞焦亡。

研究人员表示,Caspase-4是胞内细菌LPS的细胞内传感器,是感染引起的细胞凋亡的基础。目前尚不清楚caspase-4是否以及如何检测宿主来源因子来引发细胞焦亡。

附:英文原文

Title: Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Author: Wanfeng Xu, Yuan Che, Quan Zhang, Hai Huang, Chujie Ding, Yun Wang, Guangji Wang, Lijuan Cao, Haiping Hao

Issue&Volume: 2020-12-11

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

DOI: 10.1016/j.cmet.2020.11.018

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30653-7

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx