Calpain-mediated X-linked inhibitor of apoptosis degradation in neutrophil apoptosis and its impairment in chronic neutrophilic leukemia

Susumu Kobayashi, Kouhei Yamashita, Tomoharu Takeoka, Tetsuya Ohtsuki, Yasuyuki Suzuki, Ryosuke Takahashi, Kokichi Yamamoto, Scott H. Kaufmann, Takashi Uchiyama, Masataka Sasada, Atsushi Takahashi

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)33968-33977
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number37
DOIs
StatePublished - Sep 13 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kobayashi, S., Yamashita, K., Takeoka, T., Ohtsuki, T., Suzuki, Y., Takahashi, R., Yamamoto, K., Kaufmann, S. H., Uchiyama, T., Sasada, M., & Takahashi, A. (2002). Calpain-mediated X-linked inhibitor of apoptosis degradation in neutrophil apoptosis and its impairment in chronic neutrophilic leukemia. Journal of Biological Chemistry, 277(37), 33968-33977. https://doi.org/10.1074/jbc.M203350200