颗粒酶A诱导Caspases非依赖性细胞死亡

Granzyme A Induces a Cell Death Pathway Independently of Caspases Activation

颗粒酶A(granzyme A,GzmA),是存在于细胞毒性T淋巴细胞(CTL)和天然杀伤细胞(NK细胞)的细胞毒颗粒中含量最多的一种丝氨酸蛋白酶,在穿孔素(perforin)协同作用下通过颗粒胞吐(granule exocytosis)释放进入在杀伤细胞和靶细胞之间形成的免疫突触(immunological synapse),然后进入靶细胞的细胞浆,并在细胞核聚集,诱导一种caspases非依赖性细胞死亡。GzmA靶向作用于一种与内质网结合的特殊的复合体——SET复合体,其包含3种GzmA底物:核小体装配蛋白SET、DNA结合蛋白HMG-2、具有碱基切除修复作用的核酸内切酶Apel。SET复合体还含有一种抑癌蛋白pp32和一种具有脱氧核糖核酸酶(DNase)活性的NM23-H1。当GzmA作用于SET复合体时释放出NM23-H1并激活其DNase活性,也阻断了Apel对DNA损伤的修复作用,在DNA上形成单链的缺刻。这是一种新发现的由GzmA诱导的细胞凋亡途径。

Granzyme A, the most abundant serine protease in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, is released into the immunological synapse formed between the killer cell and its target, delivered to the cytosol of target cells via perforin, concentrate in target cell nuclei, and induces caspases-independent cell death. A special target of the granzyme A cell death pathway is an endoplasmic reticulum-associated complex, called the SET complex, which contains three granzyme A substrates, the nucleosome assembly protein SET, the DNA-binding protein HMG-2, and the base excision repair endonuclease Apel. The SET complex also contains the tumor suppressor protein pp32 and the granzyme A-activated DNase NM23-H1, which is inhibited by SET. Granzyme A cleavage of SET releases the NM23-H1. Cleavage of Apel by granzyme A interferes with the ability of the target cell to repair itself. This is a novel cell death pathway initiated by granzyme A.