biostudies-literatureBai MNHLBI NIH HHSNIGMS NIH HHS897https://www.ebi.ac.uk/biostudies/studies/S-EPMC5832864biostudies-literatureUnknown9(1)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 anNature communicationsConserved roles of C. elegans and human MANFs in sulfatide binding and cytoprotection.PMC5832864R00 HL116654R01 GM117461Hnizda AFeng LVozdek RKuchar LWang BLi TWood CZhang YBai MJiang CMa DKDang YfalseConserved roles of C. elegans and human MANFs in sulfatide binding and cytoprotection.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 an2018-01-01T00:00:00Z2018 Mar2026-05-06T03:52:14.072Z2026-04-27T03:08:42.853ZS-EPMC58328642949705710.1038/s41467-018-03355-0