Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity
Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity
复制标题
Granzyme K 降解氧化还原/DNA 修复酶 Ape1，引发靶细胞的氧化应激，从而导致细胞毒性。
DOI：
10.1016/j.molimm.2007.11.020
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发表时间：
2008-04-01
影响因子：
3.6
通讯作者：
Fan, Zusen
中科院分区：
文献类型：
--
作者：
Guo, Yuming;Chen, Jun;Fan, Zusen
颗粒酶K（GzmK）和颗粒酶A（GzmA）是仅有的两种类胰蛋白酶。类胰蛋白酶活性对于细胞毒性T淋巴细胞（CTL）/自然杀伤（NK）细胞介导的细胞溶解是必需的。颗粒酶K可能是拯救颗粒酶A活性的有效颗粒酶。颗粒酶K在CD 56（高）NK细胞、记忆性CD 8（+）T细胞和CD 56（+）T细胞中以高水平表达。我们最近证明，人颗粒酶K诱导快速细胞死亡的磷脂酰丝氨酸，核形态学的变化和单链DNA缺口的快速外化。此外，颗粒酶K可以诱导快速活性氧（ROS）的产生和线粒体内膜电位的崩溃。阻断活性氧簇积累可抑制颗粒酶K诱导的细胞死亡。然而，活性氧是如何在颗粒酶K介导的细胞凋亡中产生的尚不清楚。在这里，我们发现氧化还原因子-1/脱嘌呤脱嘧啶核酸内切酶Ape]可以拮抗活性氧的产生。Ape I的过表达抑制，而沉默Ape I表达增强了用氧化试剂处理或用颗粒酶K负载的活性氧簇积累。ApeI是颗粒酶K的生理底物。颗粒酶K对Ape I的裂解促进细胞内活性氧的积累，增强颗粒酶K诱导的细胞死亡。(C)2007爱思唯尔有限公司保留所有权利。
Granzyme K (Gzm K) and granzyme A (GzmA) are the only two tryptases among all the granzymes. Tryptase activity is necessary for cytotoxic T lymphocyte (CTL)/nature killer (NK) cells-mediated cytolysis. Granzyme K might be a potent granzyme to rescue the activity of granzyme A. Granzyme K expresses at high levels in CD56(high) NK cells, memory CD8(+) T cells and CD56(+) T cells. We recently demonstrated human granzyme K induces rapid cell death with rapid externalization of phosphatidylserine, nuclear morphological changes and single-stranded DNA nicks. Moreover, Granzyme K can induce rapid reactive oxygen species (ROS) generation and collapse of mitochondrial inner membrane potential. Blockade of reactive oxygen species accumulation suppresses granzyme K-induced cell death. However, it is unknown about how reactive oxygen species generate in Granzyme K-mediated apoptosis. Here we found the redox factor-1/apurinic apyrimidinic endonuclease Ape] can antagonize reactive oxygen species generation. Overexpression of Ape I inhibits, whereas silencing Ape I expression potentiates reactive oxygen species accumulation under treatment with oxidative reagents or loading with granzyme K. Ape I is a physiological substrate of granzyme K. Ape I cleavage by granzyme K facilitates intracellular reactive oxygen species accumulation and enhances granzyme K-induced cell death. (C) 2007 Elsevier Ltd. All rights reserved.