Calpain-mediated X-linked inhibitor of apoptosis degradation in neutrophil apoptosis and its impairment in chronic neutrophilic leukemia
Calpain-mediated X-linked inhibitor of apoptosis degradation in neutrophil apoptosis and its impairment in chronic neutrophilic leukemia
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DOI：
10.1074/jbc.m203350200
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发表时间：
2002-09-13
影响因子：
4.8
通讯作者：
Takahashi, A
中科院分区：
文献类型：
--
作者：
Kobayashi, S;Yamashita, K;Takahashi, A
血液和组织中嗜中性粒细胞的数量受组成性凋亡程序性细胞死亡和吞噬细胞（如巨噬细胞）清除的控制。在这里，我们发现钙蛋白酶在体外切割X连锁的凋亡抑制因子（XIAP），产生无法抑制caspase-3的片段。这些片段在正常中性粒细胞中检测到，但不稳定且迅速降解。钙蛋白酶抑制延迟肿瘤坏死因子-α诱导的正常中性粒细胞凋亡，与钙蛋白酶在调节细胞凋亡发生中的作用一致。有趣的是，来自三名慢性嗜中性粒细胞白血病患者的中性粒细胞（一种以成熟中性粒细胞积累为特征的罕见综合征）表现出μ-钙蛋白酶表达降低、钙蛋白酶活性降低和XIAP降解受损。这些患者的中性粒细胞在自发、Fas刺激和肿瘤坏死因子-α诱导的凋亡中表现出延迟。这些观察结果表明，钙蛋白酶介导的XIAP降解有助于启动正常中性粒细胞的凋亡和功能障碍，这种调节途径可以导致病理性中性粒细胞的积累。
The number of neutrophils in the blood and tissues is controlled by constitutive apoptotic programmed cell death and clearance by phagocytes such as macrophages. Here, we found that calpains cleave the X-linked inhibitor of apoptosis (XIAP) in vitro, producing fragments that are unable to inhibit caspase-3. These fragments were detected in normal neutrophils but were unstable and rapidly degraded. Calpain inhibition delayed tumor necrosis factor-alpha-induced apoptosis of normal neutrophils, consistent with a role for calpains in regulating the onset of apoptosis. Interestingly, neutrophils from three patients with chronic neutrophilic leukemia, a rare syndrome characterized by accumulation of mature neutrophils, exhibited decreased mu-calpain expression, diminished calpain activity, and impaired XIAP degradation. Neutrophils from these patients displayed a delay in spontaneous, Fas-stimulated, and tumor necrosis factor-alpha-induced apoptosis. These observations suggest that calpain-mediated XIAP degradation contributes to initiation of apoptosis in normal neutrophils and dysfunction of this regulatory pathway can lead to pathological neutrophil accumulation.