ARF-GEP100, a guanine nucleotide-exchange protein for ADP-ribosylation factor 6, involved in the apoptotic cell death of phagocytes

DOI 34 References
  • Someya Akimasa
    Department of Host Defence and Biochemical Ressearch, Juntendo University, School of Medicine
  • Moss Joel
    Pulmonary-Critical Care Medicine Branch, NHLBI, NIH
  • Vaughan Martha
    Pulmonary-Critical Care Medicine Branch, NHLBI, NIH
  • Nagaoka Isao
    Department of Host Defence and Biochemical Ressearch, Juntendo University, School of Medicine

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  • グアニンヌクレオチド交換タンパク質(guanine nucleotide-exchange protein; GEP)によるマクロファージ様細胞のアポトーシス誘導

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ADP-ribosylation factors(ARFs) are 20-kDa GTP-binding proteins involved in the vesicular trafficking, the activation of phospholipase D and phosphatidylinositol 4-phosphate 5-kinase, and the modulation of phagocyte functions. Like other GTP-binding proteins, ARFs cycle between GTP-bound, active and GDP-bound, inactive status. Guanine nucleotide-exchange proteins(GEPs), which catalyze the change of bound GDP for GTP, are necessary for the activation of ARFs. Previously, we found a novel GEP with 100kDa, named ARF-GEP100. In this study, we elucidated the role in ARF-GEP100 on phagocyte functions by transfection of ARF-GEP100.<BR>Overexpression of ARF-GEP100 induced apoptosis of mouse macrophage RAW264.7 cells and phorbol 12- myristate 13-acetate treated human monocyte U937 cells, which could be detected by morphological changes (nuclear condensation and formation of apoptotic bodies), annexin V-staining and TUNEL assay. ARF-GEP100- induced apoptosis was not inhibited by a caspase inhibitor zVAD-FMK. Furthermore, mutant analysis of ARFGEP100 revealed that two regions (N- and C- termini) of ARF-GEP100 were essential for the induction of apoptosis, but the mutant defective in GDP-GTP exchange domain induced apoptosis. These results suggest that ARFGEP100 induces apoptosis of monocytic phagocytes independent of both the caspase activation and GDP-GTP exchange activity.

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