ID MANF_CAEEL Reviewed; 168 AA. AC Q9N3B0; DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot. DT 24-JAN-2001, sequence version 2. DT 27-MAR-2024, entry version 119. DE RecName: Full=Mesencephalic astrocyte-derived neurotrophic factor homolog {ECO:0000312|WormBase:Y54G2A.23}; DE AltName: Full=ARMET-like protein; DE AltName: Full=MANF/CDNF-like protein; DE Flags: Precursor; GN Name=manf-1 {ECO:0000303|PubMed:29497057, GN ECO:0000312|WormBase:Y54G2A.23}; GN ORFNames=Y54G2A.23 {ECO:0000312|WormBase:Y54G2A.23}; OS Caenorhabditis elegans. OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida; OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae; OC Caenorhabditis. OX NCBI_TaxID=6239; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Bristol N2; RX PubMed=9851916; DOI=10.1126/science.282.5396.2012; RG The C. elegans sequencing consortium; RT "Genome sequence of the nematode C. elegans: a platform for investigating RT biology."; RL Science 282:2012-2018(1998). RN [2] RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND DISRUPTION RP PHENOTYPE. RX PubMed=30147641; DOI=10.3389/fnins.2018.00544; RA Richman C., Rashid S., Prashar S., Mishra R., Selvaganapathy P.R., RA Gupta B.P.; RT "C. elegans MANF Homolog Is Necessary for the Protection of Dopaminergic RT Neurons and ER Unfolded Protein Response."; RL Front. Neurosci. 12:544-544(2018). RN [3] RP FUNCTION, TISSUE SPECIFICITY, INDUCTION, DISRUPTION PHENOTYPE, AND RP MUTAGENESIS OF SER-75 AND CYS-146. RX PubMed=29497057; DOI=10.1038/s41467-018-03355-0; RA Bai M., Vozdek R., Hnizda A., Jiang C., Wang B., Kuchar L., Li T., RA Zhang Y., Wood C., Feng L., Dang Y., Ma D.K.; RT "Conserved roles of C. elegans and human MANFs in sulfatide binding and RT cytoprotection."; RL Nat. Commun. 9:897-897(2018). CC -!- FUNCTION: Inhibits endoplasmic reticulum (ER) stress response (By CC similarity). Retained in the ER under normal conditions and is up- CC regulated and secreted by the ER in response to ER stress and hypoxia CC (By similarity). Following secretion by the ER, directly binds to 3-O- CC sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane CC of target cells (PubMed:29497057). Sulfatide binding promotes its CC cellular uptake by endocytosis, and is required for its role in CC alleviating ER stress under ER stress conditions (By similarity). Has a CC neuroprotective role, ensuring survival of dopaminergic neurons during CC normal growth (PubMed:30147641). {ECO:0000250|UniProtKB:P55145, CC ECO:0000269|PubMed:29497057, ECO:0000269|PubMed:30147641}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P55145}. CC Endoplasmic reticulum lumen {ECO:0000250|UniProtKB:P55145}. CC Note=Retained in the endoplasmic reticulum (ER) under normal CC conditions. Up-regulated and secreted by the ER in response to ER CC stress. {ECO:0000250|UniProtKB:P55145}. CC -!- TISSUE SPECIFICITY: Expressed in the intestine, spermatheca and nervous CC system (PubMed:30147641, PubMed:29497057). Expressed in the hypoderm CC (PubMed:29497057). Expressed in structures of the excretory system CC (PubMed:30147641). Not expressed in the male gonad (PubMed:30147641). CC {ECO:0000269|PubMed:29497057, ECO:0000269|PubMed:30147641}. CC -!- DEVELOPMENTAL STAGE: Expressed throughout development, but expression CC declines with age (PubMed:30147641). Expressed in regions corresponding CC to intestinal cells and the body wall muscle quadrant in gastrulating CC embryos, and this continues throughout all larval stages and into CC adulthood in most tissues except gonadal cells (PubMed:30147641). In L4 CC stage larva, expressed in pharyngeal and vulval muscles CC (PubMed:30147641). {ECO:0000269|PubMed:30147641}. CC -!- INDUCTION: By endoplasmic reticulum stress. CC {ECO:0000305|PubMed:29497057}. CC -!- DISRUPTION PHENOTYPE: Animals are viable, and despite a delay in growth CC rate, appear healthy and have a normal lifespan (PubMed:30147641). No CC defects in the axon formation or guidance of dopaminergic, GABAergic or CC serotinergic neurons (PubMed:30147641). However, there is an age- CC dependent decline in the number of viable dopaminergic neurons under CC normal growth conditions (PubMed:30147641). Up-regulation of ER stress CC response protein hsp-4 in the intestine, hypodermis and spermatheca CC (PubMed:30147641). RNAi-mediated knockdown results in up-regulation of CC hsp-4 in the intestine and pharyngeal epithelium (PubMed:29497057). CC {ECO:0000269|PubMed:29497057, ECO:0000269|PubMed:30147641}. CC -!- SIMILARITY: Belongs to the ARMET family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; BX284604; CCD83510.1; -; Genomic_DNA. DR RefSeq; NP_500273.2; NM_067872.5. DR AlphaFoldDB; Q9N3B0; -. DR SMR; Q9N3B0; -. DR BioGRID; 42219; 3. DR STRING; 6239.Y54G2A.23.1; -. DR EPD; Q9N3B0; -. DR PaxDb; 6239-Y54G2A-23; -. DR PeptideAtlas; Q9N3B0; -. DR EnsemblMetazoa; Y54G2A.23.1; Y54G2A.23.1; WBGene00021888. DR GeneID; 177074; -. DR KEGG; cel:CELE_Y54G2A.23; -. DR UCSC; Y54G2A.23.1; c. elegans. DR AGR; WB:WBGene00021888; -. DR WormBase; Y54G2A.23; CE30049; WBGene00021888; manf-1. DR eggNOG; KOG4154; Eukaryota. DR GeneTree; ENSGT00390000007160; -. DR HOGENOM; CLU_099080_1_0_1; -. DR InParanoid; Q9N3B0; -. DR OMA; WSMPADK; -. DR OrthoDB; 49731at2759; -. DR PhylomeDB; Q9N3B0; -. DR Reactome; R-CEL-114608; Platelet degranulation. DR PRO; PR:Q9N3B0; -. DR Proteomes; UP000001940; Chromosome IV. DR Bgee; WBGene00021888; Expressed in pharyngeal muscle cell (C elegans) and 3 other cell types or tissues. DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central. DR GO; GO:0005788; C:endoplasmic reticulum lumen; IEA:UniProtKB-SubCell. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0120146; F:sulfatide binding; IPI:UniProtKB. DR GO; GO:0048589; P:developmental growth; IMP:UniProtKB. DR GO; GO:0071542; P:dopaminergic neuron differentiation; IBA:GO_Central. DR GO; GO:0031175; P:neuron projection development; IBA:GO_Central. DR GO; GO:1905897; P:regulation of response to endoplasmic reticulum stress; IMP:UniProtKB. DR Gene3D; 1.10.720.30; SAP domain; 1. DR Gene3D; 1.10.225.10; Saposin-like; 1. DR InterPro; IPR045333; ARMET-like. DR InterPro; IPR019345; ARMET_C. DR InterPro; IPR045332; ARMET_N. DR InterPro; IPR036361; SAP_dom_sf. DR PANTHER; PTHR12990; ARMET-LIKE PROTEIN; 1. DR PANTHER; PTHR12990:SF5; MESENCEPHALIC ASTROCYTE-DERIVED NEUROTROPHIC FACTOR HOMOLOG; 1. DR Pfam; PF10208; ARMET_C; 1. DR Pfam; PF20145; ARMET_N; 1. DR SUPFAM; SSF68906; SAP domain; 1. PE 1: Evidence at protein level; KW Disulfide bond; Endoplasmic reticulum; Lipid-binding; Reference proteome; KW Secreted; Signal; Stress response. FT SIGNAL 1..17 FT /evidence="ECO:0000255" FT CHAIN 18..168 FT /note="Mesencephalic astrocyte-derived neurotrophic factor FT homolog" FT /id="PRO_0000002307" FT DISULFID 22..109 FT /evidence="ECO:0000250|UniProtKB:P55145" FT DISULFID 25..97 FT /evidence="ECO:0000250|UniProtKB:P55145" FT DISULFID 55..66 FT /evidence="ECO:0000250|UniProtKB:P55145" FT DISULFID 143..146 FT /evidence="ECO:0000250|UniProtKB:P55145" FT MUTAGEN 75 FT /note="S->L: In dma1; results in up-regulation of ER stress FT response protein hsp-4 in the intestine and pharyngeal FT epithelium. Elevated expression of hsp-4 is suppressed in FT xbp-1 or ire-1 RNAi-mediated knockdown animals." FT /evidence="ECO:0000269|PubMed:29497057" FT MUTAGEN 146 FT /note="C->G: Does not rescue the elevated expression of the FT ER stress response protein hsp-4 in the dma1 mutant." FT /evidence="ECO:0000269|PubMed:29497057" SQ SEQUENCE 168 AA; 18969 MW; 5A24379E860A6628 CRC64; MSRLVLLISL VIVVASAAAP QCEVCKKVLD DVMAKVPAGD KSKPDAIGKV IREHCETTRN KENKFCFYIG ALPESATSIM NEVTKPLSWS MPTEKVCLEK LKGKDAQICE LKYDKPLDWK TIDLKKMRVK ELKNILGEWG EVCKGCTEKA ELIKRIEELK PKYVKEEL //