The NG2 Proteoglycan Protects Oligodendrocyte Precursor Cells against Oxidative Stress via Interaction with OMI/HtrA2.
The NG2 proteoglycan is characteristically expressed by oligodendrocyte progenitor cells (OPC) and also by aggressive brain tumours highly resistant to chemo- and radiation therapy. Oligodendrocyte-lineage cells are particularly sensitive to stress resulting in cell death in white matter after hypoxic or ischemic insults of premature infants and destruction of OPC in some types of Multiple Sclerosis lesions. Here we show that the NG2 proteoglycan binds OMI/HtrA2, a mitochondrial serine protease which is released from damaged mitochondria into the cytosol in response to stress. In the cytosol, OMI/HtrA2 initiates apoptosis by proteolytic degradation of anti-apoptotic factors. OPC in which NG2 has been downregulated by siRNA, or OPC from the NG2-knockout mouse show an increased sensitivity to oxidative stress evidenced by increased cell death. The proapoptotic protease activity of OMI/HtrA2 in the cytosol can be reduced by the interaction with NG2. Human glioma expressing high levels of NG2 are less sensitive to oxidative stress than those with lower NG2 expression and reducing NG2 expression by siRNA increases cell death in response to oxidative stress. Binding of NG2 to OMI/HtrA2 may thus help protect cells against oxidative stress-induced cell death. This interaction is likely to contribute to the high chemo- and radioresistance of glioma.
Department of Biology, Molecular Cell Biology, Johannes Gutenberg University, Mainz, Germany.
Frank
F
Maus
Department of Biology, Molecular Cell Biology, Johannes Gutenberg University, Mainz, Germany.
Dominik
D
Sakry
Department of Biology, Molecular Cell Biology, Johannes Gutenberg University, Mainz, Germany.
Fabien
F
Binamé
Department of Biology, Molecular Cell Biology, Johannes Gutenberg University, Mainz, Germany; Institute for Molecular Medicine, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany.
Khalad
K
Karram
Research Center for Immune Therapy, Institute for Immunology, Johannes Gutenberg University of Mainz, Medical Center Mainz, Mainz, Germany.
Krishnaraj
K
Rajalingam
Cambridge University, Dept. Clinical Neurosciences, Division of Neurosurgery, Cambridge, United Kingdom.
Colin
C
Watts
Cambridge University, Dept. Clinical Neurosciences, Division of Neurosurgery, Cambridge, United Kingdom.
Richard
R
Heywood
Clinical and Experimental Neuroscience, Luxembourg Center for Systems Biomedicine, University of Luxembourg and Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg; Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, and German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
Rejko
R
Krüger
Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
Judith
J
Stegmüller
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Hauke B
HB
Werner
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Klaus-Armin
KA
Nave
Department of Biology, Molecular Cell Biology, Johannes Gutenberg University, Mainz, Germany.
Eva-Maria
EM
Krämer-Albers
Department of Biology, Molecular Cell Biology, Johannes Gutenberg University, Mainz, Germany.
Jacqueline
J
Trotter
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011485:Protein Binding; D011509:Proteoglycans / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099216:Chondroitin Sulfate Proteoglycan 4
D057134:Antibodies, Neutralizing; D000941:Antigens; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006861:Hydrogen Peroxide; D024101:Mitochondrial Proteins; D011509:Proteoglycans; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; D000099216:Chondroitin Sulfate Proteoglycan 4; C000615914:HTRA2 protein, human; C000615915:Htra2 protein, mouse