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 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.
Kobayashi
Susumu
S
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Yamashita
Kouhei
K
Takeoka
Tomoharu
T
Ohtsuki
Tetsuya
T
Suzuki
Yasuyuki
Y
Takahashi
Ryosuke
R
Yamamoto
Kokichi
K
Kaufmann
Scott H
SH
Uchiyama
Takashi
T
Sasada
Masataka
M
Takahashi
Atsushi
A
D000368:Aged; D017209:Apoptosis; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D006801:Humans; D015467:Leukemia, Neutrophilic, Chronic / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein
D061945:Caspase Inhibitors; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003513:Cycloheximide; C505407:CASP3 protein, human; D002154:Calpain; D053148:Caspase 3