TY  - JOUR
AU  - Maus, Frank
AU  - Sakry, Dominik
AU  - Binamé, Fabien
AU  - Karram, Khalad
AU  - Rajalingam, Krishnaraj
AU  - Watts, Colin
AU  - Heywood, Richard
AU  - Krüger, Rejko
AU  - Stegmüller, Judith
AU  - Werner, Hauke B
AU  - Nave, Klaus-Armin
AU  - Krämer-Albers, Eva-Maria
AU  - Trotter, Jacqueline
TI  - The NG2 Proteoglycan Protects Oligodendrocyte Precursor Cells against Oxidative Stress via Interaction with OMI/HtrA2.
JO  - PLOS ONE
VL  - 10
IS  - 9
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-04413
SP  - e0137311
PY  - 2015
AB  - 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.
KW  - Animals
KW  - Antibodies, Neutralizing: pharmacology
KW  - Antigens: genetics
KW  - Antigens: metabolism
KW  - Apoptosis: drug effects
KW  - Brain Neoplasms: genetics
KW  - Brain Neoplasms: metabolism
KW  - Brain Neoplasms: pathology
KW  - Cell Line, Tumor
KW  - Cerebellum: drug effects
KW  - Cerebellum: metabolism
KW  - Cerebellum: pathology
KW  - Cytosol: drug effects
KW  - Cytosol: metabolism
KW  - Gene Expression Regulation, Neoplastic
KW  - Glioblastoma: genetics
KW  - Glioblastoma: metabolism
KW  - Glioblastoma: pathology
KW  - High-Temperature Requirement A Serine Peptidase 2
KW  - Humans
KW  - Hydrogen Peroxide: pharmacology
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Mitochondrial Proteins: genetics
KW  - Mitochondrial Proteins: metabolism
KW  - Oxidative Stress
KW  - Primary Cell Culture
KW  - Protein Binding
KW  - Proteoglycans: antagonists & inhibitors
KW  - Proteoglycans: genetics
KW  - Proteoglycans: metabolism
KW  - RNA, Small Interfering: genetics
KW  - RNA, Small Interfering: metabolism
KW  - Serine Endopeptidases: genetics
KW  - Serine Endopeptidases: metabolism
KW  - Signal Transduction
KW  - Antibodies, Neutralizing (NLM Chemicals)
KW  - Antigens (NLM Chemicals)
KW  - Mitochondrial Proteins (NLM Chemicals)
KW  - Proteoglycans (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - chondroitin sulfate proteoglycan 4 (NLM Chemicals)
KW  - Hydrogen Peroxide (NLM Chemicals)
KW  - Serine Endopeptidases (NLM Chemicals)
KW  - HTRA2 protein, human (NLM Chemicals)
KW  - High-Temperature Requirement A Serine Peptidase 2 (NLM Chemicals)
KW  - Htra2 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26340347
C2  - pmc:PMC4560422
DO  - DOI:10.1371/journal.pone.0137311
UR  - https://pub.dzne.de/record/138091
ER  -