Specific depletion of GGA2 causes cathepsin D missorting in HeLa cells

  • Hida Tatsuhiro
    Department of Conservative Dentistry, Osaka University Faculty of Dentistry
  • Ikeda Hiroko
    Department of Anatomy and Histology, Fukushima Medical University, School of Medicine
  • Kametaka Satoshi
    Department of Anatomy and Histology, Fukushima Medical University, School of Medicine
  • Akazawa Chihiro
    Department of Neurochemistry, National Institute of Neuroscience
  • Kohsaka Shinichi
    Department of Neurochemistry, National Institute of Neuroscience
  • Ebisu Shigeyuki
    Department of Conservative Dentistry, Osaka University Faculty of Dentistry
  • Uchiyama Yasuo
    Department of Cell Biology and Neuroscience (A1), Osaka University Graduate School of Medicine
  • Waguri Satoshi
    Department of Anatomy and Histology, Fukushima Medical University, School of Medicine

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Three mammalian GGAs (Golgi-localized, γ-ear-containing, ARF-binding proteins), GGA1, 2, and 3 have been implicated in the sorting of mannose 6-phosphate receptor (MPR). To investigate the distinct roles of GGA2 in lysosomal enzyme transport, we established two stable cell lines that had a reduced expression of GGA2 by RNA interference. The expression levels of GGA2 were approximately 5% of the control levels, whereas those of non-targeted GGA1 and GGA3 were not apparently reduced. The depletion of GGA2 did not cause changes in the overall distribution of GGA1, GGA3, cation-dependent MPR, or cation-independent MPR. However, the cell lines showed increased secretion of a lysosomal enzyme, cathepsin D. In addition, a moderate expression of the dominant negative VHS-GAT domain of GGA2 had no effect on the trans-Golgi network (TGN) signal of three GGAs, nor was the GGA2 signal affected by the expression of VHS-GAT domain of GGA1 or 3. These results suggest that GGA2 is recruited to the TGN independently of the other GGAs and is required for the efficient sorting of lysosomal enzymes.

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