肿瘤抑制因子NM23-H1是细胞毒性T淋巴细胞（CTL）介导的细胞凋亡过程中颗粒酶A激活的脱氧核糖核酸酶，而核小体组装蛋白SET是其抑制剂。

Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor.

作者信息

Fan Zusen, Beresford Paul J, Oh David Y, Zhang Dong, Lieberman Judy

机构信息

Center for Blood Research and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

出版信息

Cell. 2003 Mar 7;112(5):659-72. doi: 10.1016/s0092-8674(03)00150-8.

DOI:10.1016/s0092-8674(03)00150-8

PMID:12628186

Abstract

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.

摘要

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。