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Nat Commun. 2018 Mar 1;9(1):897. doi: 10.1038/s41467-018-03355-0.

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

Author information

1
Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, 94158, USA.
2
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10, Prague 6, Czech Republic.
3
Key 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.
4
Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, 12808, Czech Republic.
5
Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China.
6
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, 94305, USA.
7
Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, 94158, USA. Dengke.Ma@ucsf.edu.

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.

PMID:
29497057
PMCID:
PMC5832864
DOI:
10.1038/s41467-018-03355-0
[Indexed for MEDLINE]
Free PMC Article

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