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Conserved roles of C. elegans and human MANFs in sulfatide binding and cytoprotection

Author

Listed:
  • Meirong Bai

    (University of California San Francisco)

  • Roman Vozdek

    (University of California San Francisco)

  • Aleš Hnízda

    (Academy of Sciences of the Czech Republic)

  • Chenxiao Jiang

    (Fudan University)

  • Bingying Wang

    (University of California San Francisco)

  • Ladislav Kuchar

    (Charles University and General University Hospital in Prague)

  • Tiejun Li

    (Second Military Medical University)

  • Yuefan Zhang

    (Second Military Medical University)

  • Chase Wood

    (Stanford University)

  • Liang Feng

    (Stanford University)

  • Yongjun Dang

    (Fudan University)

  • Dengke K. Ma

    (University of California San Francisco)

Abstract

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons and cardiomyocytes from ER stress and apoptosis. The mechanism of action of extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal ER stress response, we identified the gene Y54G2A.23 as the evolutionarily conserved C. elegans MANF orthologue. We find that MANF binds to the lipid sulfatide, also known as 3-O-sulfogalactosylceramide present in serum and outer-cell membrane leaflets, directly in isolated forms and in reconstituted lipid micelles. Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. Heightened ER stress responses of MANF-null C. elegans mutants and mammalian cells are alleviated by human MANF in a sulfatide-dependent manner. Our results demonstrate conserved roles of MANF in sulfatide binding and ER stress response, supporting sulfatide as a long-sought lipid mediator of MANF’s cytoprotection.

Suggested Citation

  • Meirong Bai & Roman Vozdek & Aleš Hnízda & Chenxiao Jiang & Bingying Wang & Ladislav Kuchar & Tiejun Li & Yuefan Zhang & Chase Wood & Liang Feng & Yongjun Dang & Dengke K. Ma, 2018. "Conserved roles of C. elegans and human MANFs in sulfatide binding and cytoprotection," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03355-0
    DOI: 10.1038/s41467-018-03355-0
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