Calpain-mediated X-linked Inhibitor of Apoptosis Degradation in Neutrophil Apoptosis and Its Impairment in Chronic Neutrophilic Leukemia

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 ca...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-09, Vol.277 (37), p.33968-33977
Main Authors: Kobayashi, Susumu, Yamashita, Kouhei, Takeoka, Tomoharu, Ohtsuki, Tetsuya, Suzuki, Yasuyuki, Takahashi, Ryosuke, Yamamoto, Kokichi, Kaufmann, Scott H., Uchiyama, Takashi, Sasada, Masataka, Takahashi, Atsushi
Format: Article
Language:English
Subjects:
Aged
Apoptosis
Calpain - antagonists & inhibitors
Calpain - physiology
Caspase 3
Caspase Inhibitors
Cycloheximide - pharmacology
Female
Humans
Leukemia, Neutrophilic, Chronic - blood
Male
Middle Aged
Neutrophils - metabolism
Proteins - metabolism
Tumor Necrosis Factor-alpha - pharmacology
X-Linked Inhibitor of Apoptosis Protein
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Summary: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-α-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 μ-calpain expression, diminished calpain activity, and impaired XIAP degradation. Neutrophils from these patients displayed a delay in spontaneous, Fas-stimulated, and tumor necrosis factor-α-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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M203350200