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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, View ORCID ProfileDengke K. Ma
doi: https://doi.org/10.1101/263731
Meirong Bai
1Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA 94158
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Roman Vozdek
1Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA 94158
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Aleš Hnízda
2Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic
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Chenxiao Jiang
3Key Laboratory of Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
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Bingying Wang
1Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA 94158
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Ladislav Kuchar
4Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Tiejun Li
5Department of Pharmacology, Second Military Medical University, Shanghai, China
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Yuefan Zhang
5Department of Pharmacology, Second Military Medical University, Shanghai, China
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Chase Wood
6Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305
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Liang Feng
6Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305
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Yongjun Dang
3Key Laboratory of Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
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Dengke K. Ma
1Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA 94158
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  • ORCID record for Dengke K. Ma
  • For correspondence: Dengke.Ma@ucsf.edu
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Abstract

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protect 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.

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Posted February 11, 2018.
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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, Dengke K. Ma
bioRxiv 263731; doi: https://doi.org/10.1101/263731
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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, Dengke K. Ma
bioRxiv 263731; doi: https://doi.org/10.1101/263731

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