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

Meirong Bai, Roman Vozdek, Aleš Hnízda, Chenxiao Jiang, Bingying Wang, Ladislav Kuchar, Tiejun Li, Yuefan Zhang, Chase Wood, Liang Feng, Yongjun Dang and Dengke K. Ma ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03355-0

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