Granzyme B-mediated apoptosis--the elephant and the blind men?
Granzyme B-mediated apoptosis--the elephant and the blind men?
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颗粒酶 B 介导的细胞凋亡——大象和盲人？
DOI：
10.1038/sj.cdd.4401381
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Raja,SM
中科院分区：
文献类型：
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作者：
Froelich,CJ;Metkar,SS;Raja,SM
细胞毒性细胞颗粒介导的细胞凋亡是一种独特的细胞信号传导形式，需要在细胞内递送颗粒相关丝氨酸蛋白酶（颗粒酶）。最近的研究表明，细胞毒性细胞分泌由多种颗粒酶和穿孔素（PFN）组成的大复合物，这些颗粒酶和穿孔素（PFN）与名为丝氨酸的支架蛋白聚糖结合。 1 在颗粒蛋白酶中，颗粒酶 B (GrB) 的细胞凋亡诱导机制似乎最简单。据报道，GrB 可在体外裂解大量半胱天冬酶（-3、-6、-7、-8-9 和-10）2，这激发了人们的认识，即该蛋白酶能够通过激活体内多个家族成员来引发死亡。更复杂的是，颗粒酶还可能通过消化结构蛋白和调节蛋白来杀死病毒。 3, 4 最后，据报道，GrB 通过裂解仅 BH3 的促凋亡 Bcl-2 家族成员 Bid，通过以线粒体为中心的途径启动死亡。 5-10 这些结果共同表明，颗粒酶具有多方面的潜力，可通过以下机制确保靶细胞死亡：(1) caspase 驱动，(2) BH3 蛋白驱动，(3) 由于关键细胞蛋白的裂解。然而，这些观察结果需要与以下发现相一致：Bcl-2 可重复抑制 GrB 介导的细胞凋亡（定义为靶细胞中克隆形成潜力的丧失）。据预测，Bcl-2 可以防止线粒体攻击，但通过半胱天冬酶以及细胞蛋白质消化启动的细胞凋亡防御机制更难以理解。
Cytotoxic cell granule-mediated apoptosis is a unique form of cell signaling that entails the intracellular delivery of granuleassociated serine proteases (granzymes). Recent work has suggested that the cytotoxic cell secretes macrocomplexes consisting of multiple granzymes and Perforin (PFN) bound to a scaffold proteoglycan named serglycin. 1 Among the granule proteases, the mechanism of apoptosis induction would seem most straightforward for granzyme B (GrB). GrB has been reported to cleave numerous caspases in vitro (-3,-6,-7,-8-9 and-10) 2 stimulating the notion that the protease is able to initiate death by activating multiple family members in vivo. To complicate matters, the granzyme might also kill by digesting structural and regulatory proteins. 3, 4 Finally, GrB has been reported to initiate death through a mitochondria-centered pathway by cleaving the BH3-only proapoptotic Bcl-2 family member, Bid. 5–10 Together the results imply that the granzyme has a multifaceted potential to ensure target cell death through mechanisms that are:(1) caspase-driven,(2) BH3 protein-driven, and (3) due to cleavage of crucial cellular proteins. These observations, however, require reconciliation with the finding that Bcl-2 reproducibly inhibits GrB-mediated apoptosis as defined by loss of clonogenic potential in the target cells. Bcl-2 is predicted to protect against a mitochondrial assault, but defense against apoptosis initiated through caspases as well as digestion of cellular proteins is more difficult to comprehend.