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Published online before print July 28, 2006

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(Journal of Leukocyte Biology. 2006;80:915-921.)
© 2006 by Society for Leukocyte Biology

Involvement of a guanine nucleotide-exchange protein, ARF-GEP₁₀₀/BRAG2a, in the apoptotic cell death of monocytic phagocytes

Akimasa Someya^*,1, Joel Moss and Isao Nagaoka^*

^* Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, Tokyo, Japan; and
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

¹ Correspondence: Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: someya{at}med.juntendo.ac.jp

We previous identified adenosine 5'-diphosphate-ribosylation factor (ARF)-guanine nucleotide-exchange protein, 100 kDa (GEP₁₀₀), as a novel GEP with a molecular size of 100 kDa, which preferentially activates ARF6. In this study, we examined the effect of ARF-GEP₁₀₀ on monocytic cell apoptosis. Overexpression of ARF-GEP₁₀₀ in PMA-differentiated human monocyte-macrophage-like U937 cells and mouse macrophage RAW264.7 cells induced apoptotic cell death, which was detected by morphological changes (chromatin condensation, nucleus fragmentation, and shrinking of cytoplasm), annexin V-staining, and TUNEL assay. It is interesting that a mutant lacking the Sec7 domain, which is responsible for ARF activation, was able to induce apoptosis of the target cells to the level of that of a wild-type ARF-GEP₁₀₀. Furthermore, ARF-GEP₁₀₀-silencing experiments indicated that the TNF--induced apoptosis was significantly suppressed among ARF-GEP₁₀₀-depressed cells. These observations apparently suggest that ARF-GEP₁₀₀ is involved in the induction of apoptosis in monocytic phagocytes, possibly independent of ARF activation.

Key Words: apoptosis • GEF • Sec7 domain • macrophages • siRNA