MANF_CAEEL
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 25-MAY-2022, entry version 111.
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, 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}.
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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; -.
DR EPD; Q9N3B0; -.
DR PaxDb; Q9N3B0; -.
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 CTD; 177074; -.
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; VCKKVLD; -.
DR OrthoDB; 1427430at2759; -.
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 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:1901215; P:negative regulation of neuron death; IMP:UniProtKB.
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; -; 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; PTHR12990; 1.
DR Pfam; PF10208; ARMET_C; 1.
DR Pfam; PF20145; ARMET_N; 1.
DR SUPFAM; SSF68906; SSF68906; 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
