Fan Zusen, Beresford Paul J, Oh David Y, Zhang Dong, Lieberman Judy
Center for Blood Research and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2003 Mar 7;112(5):659-72. doi: 10.1016/s0092-8674(03)00150-8.
Granzyme A (GzmA) induces a caspase-independent cell death pathway characterized by single-stranded DNA nicks and other features of apoptosis. A GzmA-activated DNase (GAAD) is in an ER associated complex containing pp32 and the GzmA substrates SET, HMG-2, and Ape1. We show that GAAD is NM23-H1, a nucleoside diphosphate kinase implicated in suppression of tumor metastasis, and its specific inhibitor (IGAAD) is SET. NM23-H1 binds to SET and is released from inhibition by GzmA cleavage of SET. After GzmA loading or CTL attack, SET and NM23-H1 translocate to the nucleus and SET is degraded, allowing NM23-H1 to nick chromosomal DNA. GzmA-treated cells with silenced NM23-H1 expression are resistant to GzmA-mediated DNA damage and cytolysis, while cells overexpressing NM23-H1 are more sensitive.
颗粒酶A（GzmA）诱导一种不依赖半胱天冬酶的细胞死亡途径，其特征为单链DNA切口和凋亡的其他特征。一种GzmA激活的脱氧核糖核酸酶（GAAD）存在于一种与内质网相关的复合物中，该复合物包含pp32以及GzmA底物SET、HMG-2和Ape1。我们发现GAAD是NM23-H1，一种与抑制肿瘤转移有关的核苷二磷酸激酶，其特异性抑制剂（IGAAD）是SET。NM23-H1与SET结合，并通过GzmA对SET的切割而解除抑制。在GzmA加载或细胞毒性T淋巴细胞攻击后，SET和NM23-H1转移至细胞核，SET被降解，使得NM23-H1能够切割染色体DNA。NM23-H1表达沉默的GzmA处理细胞对GzmA介导的DNA损伤和细胞溶解具有抗性，而过度表达NM23-H1的细胞则更敏感。
