ENDOU

Summary

ENDOU (endonuclease, poly(U) specific, HGNC:14369) is a protein-coding gene on chromosome 12q13.11, encoding Uridylate-specific endoribonuclease (P21128). Endoribonuclease that cleaves single-stranded RNAs at 5’ of uridylates and releases a product with a 2’,3’-cyclic phosphate at the 3’-end.

This gene encodes a protein with endoribonuclease activity that binds polyuridine-enriched single-stranded RNA. This gene was initially characterized based on its high expression in placenta but was mischaracterized as a serine protease. In mouse, this gene promotes tolerance to self-antigens by regulating B cell activation-induced cell death (AICD). The protein may be useful as a tumor marker. Multiple alternatively spliced transcript variants encoding distinct protein isoforms have been found for this gene.

Source: NCBI Gene 8909 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 60 total
• MANE Select transcript: NM_001172439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14369
Approved symbol	ENDOU
Name	endonuclease, poly(U) specific
Location	12q13.11
Locus type	gene with protein product
Status	Approved
Aliases	PP11, P11, PRSS26
Ensembl gene	ENSG00000111405
Ensembl biotype	protein_coding
OMIM	606720
Entrez	8909

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000229003, ENST00000422538, ENST00000545824, ENST00000551186

RefSeq mRNA: 3 — MANE Select: NM_001172439 NM_001172439, NM_001172440, NM_006025

CCDS: CCDS53784, CCDS53785, CCDS8754

Canonical transcript exons

ENST00000422538 — 10 exons

Exon	Start	End
ENSE00000737756	47717518	47717655
ENSE00000737760	47713275	47713388
ENSE00000737762	47712516	47712622
ENSE00000737765	47711633	47711775
ENSE00000888022	47718129	47718194
ENSE00001787867	47720753	47720875
ENSE00002388121	47725359	47725490
ENSE00002403545	47709734	47710919
ENSE00003469373	47716890	47717058
ENSE00003639144	47716300	47716499

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 98.30.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4167 / max 154.2665, expressed in 48 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130682	0.2164	26
130683	0.1218	20
130681	0.0397	10
130684	0.0250	6
130680	0.0138	7

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.30	gold quality
tongue squamous epithelium	UBERON:0006919	98.20	gold quality
gingival epithelium	UBERON:0001949	95.83	gold quality
gingiva	UBERON:0001828	95.57	gold quality
esophagus mucosa	UBERON:0002469	93.91	gold quality
cervix squamous epithelium	UBERON:0006922	93.38	gold quality
oral cavity	UBERON:0000167	92.81	gold quality
squamous epithelium	UBERON:0006914	92.70	gold quality
epithelium of esophagus	UBERON:0001976	91.22	gold quality
esophagus squamous epithelium	UBERON:0006920	90.80	gold quality
cervix epithelium	UBERON:0004801	90.73	gold quality
pharyngeal mucosa	UBERON:0000355	90.66	gold quality
penis	UBERON:0000989	89.86	gold quality
body of tongue	UBERON:0011876	87.31	gold quality
skin of abdomen	UBERON:0001416	86.53	gold quality
mammalian vulva	UBERON:0000997	85.79	gold quality
upper arm skin	UBERON:0004263	85.62	gold quality
skin of leg	UBERON:0001511	85.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.07	silver quality
zone of skin	UBERON:0000014	84.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.16	gold quality
vagina	UBERON:0000996	81.16	gold quality
placenta	UBERON:0001987	79.60	gold quality
esophagus	UBERON:0001043	79.06	gold quality
tongue	UBERON:0001723	78.39	gold quality
upper leg skin	UBERON:0004262	77.14	gold quality
skin of hip	UBERON:0001554	74.68	gold quality
uterine cervix	UBERON:0000002	73.58	gold quality
oviduct epithelium	UBERON:0004804	73.03	gold quality
ectocervix	UBERON:0012249	69.93	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

Literature-anchored findings (GeneRIF, showing 4)

• human placental protein 11 is an endoribonuclease (PMID:18936097)
• Connecting the dots on vertical transmission of SARS-CoV-2 using protein-protein interaction network analysis - Potential roles of placental ACE2 and ENDOU. (PMID:33197855)
• Poly(U)-specific endoribonuclease ENDOU promotes translation of human CHOP mRNA by releasing uORF element-mediated inhibition. (PMID:33511665)
• [1]H, [13]C and [15]N backbone resonance assignment of the calcium-activated EndoU endoribonuclease. (PMID:39249657)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	endou	ENSDARG00000044204
mus_musculus	Endou	ENSMUSG00000022468
rattus_norvegicus	Endou	ENSRNOG00000056446
drosophila_melanogaster	CG2145	FBGN0030251
drosophila_melanogaster	EndoU	FBGN0038381
caenorhabditis_elegans	endu-1	WBGENE00010488
caenorhabditis_elegans		WBGENE00019779

Protein

Protein identifiers

Uridylate-specific endoribonuclease — P21128 (reviewed: P21128)

Alternative names: Placental protein 11, Protein endoU

All UniProt accessions (1): P21128

UniProt curated annotations — full annotation on UniProt →

Function. Endoribonuclease that cleaves single-stranded RNAs at 5’ of uridylates and releases a product with a 2’,3’-cyclic phosphate at the 3’-end. The UU and GU sites are more efficiently cleaved than CU and AU sites. Targets mRNAs to regulate their expression.

Subunit / interactions. Monomer.

Subcellular location. Secreted.

Tissue specificity. Placental-specific, but also associated with various malignant neoplasms.

Post-translational modifications. It has been suggested that the active SMB domain may be permitted considerable disulfide bond heterogeneity or variability, thus two alternate disulfide patterns based on 3D structures are described with 1 disulfide bond conserved in both.

Similarity. Belongs to the ENDOU family.

Isoforms (3)

UniProt ID	Names	Canonical?
P21128-1	1	yes
P21128-2	2
P21128-3	3

RefSeq proteins (3): NP_001165910, NP_001165911, NP_006016 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001212	Somatomedin_B_dom	Domain
IPR018998	EndoU_C	Domain
IPR020436	SMB_chordata	Domain
IPR036024	Somatomedin_B-like_dom_sf	Homologous_superfamily
IPR037227	EndoU-like	Homologous_superfamily
IPR039787	ENDOU	Family

Pfam: PF01033, PF09412

Catalyzed reactions (Rhea), 1 shown:

• ribonucleotidyl-uridine-RNA = a 5’-end dephospho-uridine-RNA + a 3’-end 2’,3’-cyclophospho-ribonucleotide-RNA (RHEA:67792)

UniProt features (31 total): disulfide bond 14, mutagenesis site 5, domain 3, active site 3, splice variant 2, sequence conflict 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9FTW	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21128-F1	85.91	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 285; 300; 343

Disulfide bonds (14): 28–58, 38–51, 38–40, 44–50, 51–58, 90–106, 90–94, 94–124, 104–117, 104–106, 110–116, 117–124, 24–40, 24–28

Mutagenesis-validated functional residues (5):

Position	Phenotype
284	abolishes endoribonuclease activity and increases rna-binding activity.
285	abolishes endoribonuclease activity without affecting rna-binding activity.
290	abolishes endoribonuclease activity without affecting rna-binding activity.
300	abolishes endoribonuclease activity without affecting rna-binding activity.
343	strongly impairs endoribonuclease activity without affecting rna-binding activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 137 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, KYNG_DNA_DAMAGE_DN, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_MULTI_MULTICELLULAR_ORGANISM_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_CATABOLIC_PROCESS

GO Biological Process (7): proteolysis (GO:0006508), immune response (GO:0006955), female pregnancy (GO:0007565), post-transcriptional gene silencing (GO:0016441), negative regulation of lipid catabolic process (GO:0050995), signal transduction (GO:0007165), vesicle-mediated transport (GO:0016192)

GO Molecular Function (13): RNA binding (GO:0003723), RNA endonuclease activity (GO:0004521), scavenger receptor activity (GO:0005044), growth factor activity (GO:0008083), serine-type peptidase activity (GO:0008236), lyase activity (GO:0016829), manganese ion binding (GO:0030145), polysaccharide binding (GO:0030247), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), RNA nuclease activity (GO:0004540), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
catalytic activity	2
nuclease activity	2
cellular anatomical structure	2
protein metabolic process	1
immune system process	1
response to stimulus	1
multi-organism reproductive process	1
multi-multicellular organism process	1
post-transcriptional regulation of gene expression	1
negative regulation of gene expression	1
negative regulation of catabolic process	1
lipid catabolic process	1
negative regulation of lipid metabolic process	1
regulation of lipid catabolic process	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transport	1
nucleic acid binding	1
endonuclease activity	1
RNA nuclease activity	1
cargo receptor activity	1
receptor ligand activity	1
peptidase activity	1
serine hydrolase activity	1
transition metal ion binding	1
carbohydrate binding	1
catalytic activity, acting on a nucleic acid	1
catalytic activity, acting on RNA	1
cation binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENDOU	LGALS13	Q9UHV8	706
ENDOU	HEBP2	Q9Y5Z4	641
ENDOU	PPP1CA	P08129	583
ENDOU	NUTF2	P13662	582
ENDOU	TCEAL1	Q15170	582
ENDOU	PPP6C	O00743	576
ENDOU	PAEP	P09466	574
ENDOU	TPK1	Q9H3S4	540
ENDOU	PPEF1	O14829	540
ENDOU	SH2D3A	Q9BRG2	479
ENDOU	IGFBP1	P08833	479
ENDOU	STMN1	P16949	447
ENDOU	DEDD	O75618	440
ENDOU	SH2D3C	Q8N5H7	433
ENDOU	IFIH1	Q9BYX4	423

IntAct

25 interactions, top by confidence:

A	B	Type	Score
KLHL11	PIPSL	psi-mi:“MI:0914”(association)	0.350
SRRT	A2ML1	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
RIPPLY3	A2ML1	psi-mi:“MI:0914”(association)	0.350
PRXL2A	A2ML1	psi-mi:“MI:0914”(association)	0.350
STK11	A2ML1	psi-mi:“MI:0914”(association)	0.350
FCF1	SULT2B1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
NRSN1	IGLC7	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
PIGT	A2ML1	psi-mi:“MI:0914”(association)	0.350
C18orf21	A2ML1	psi-mi:“MI:0914”(association)	0.350
PINK1	A2ML1	psi-mi:“MI:0914”(association)	0.350
FNDC5	A2ML1	psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350
SARAF	A2ML1	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
ZC3HC1	SULT2B1	psi-mi:“MI:0914”(association)	0.350
SLC37A4	KLK10	psi-mi:“MI:0914”(association)	0.350
RSRP1	A2ML1	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS), ENDOU (Affinity Capture-MS)

ESM2 similar proteins: A0A0A2J9B0, A1L237, A4USB4, A6QLQ8, A8E624, A8E627, B1H3D5, B1WBB4, D4ANL2, D4DE03, E5D3Z8, O16025, O80452, O82122, P04176, P08170, P09918, P0CE81, P14856, P17276, P21128, P34387, P34508, P38416, P40514, Q17778, Q1LUM3, Q1W694, Q1W695, Q21109, Q27Q54, Q2XQ09, Q3V188, Q4ZFU1, Q54PA4, Q553Y1, Q58A42, Q5AKB1, Q5B3K6, Q6BHB1

Diamond homologs: A1L237, A6QLQ8, A8E624, A8E627, B1H3D5, B1WBB4, P21128, Q1LUM3, Q21109, Q3V188, Q503V9, Q8JFY9, Q9PTU6, Q9VF14, Q9VZ49, Q92954, Q9JM99, P04004, O55123, O70138, O88766, P07152, P22458, P28863, P29788, P48819, P08254, P39900, P50281, P53690, P79227, Q10739, Q28397, Q5RES1, Q90611, Q99PW6, Q9R0S2, Q9XT90, Q9Y5R2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

60 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1461 predictions. Top by Δscore:

Variant	Effect	Δscore
12:47711631:A:AC	donor_gain	1.0000
12:47711632:C:CC	donor_gain	1.0000
12:47711632:CA:C	donor_gain	1.0000
12:47711681:A:C	donor_gain	1.0000
12:47711717:T:TA	donor_gain	1.0000
12:47711771:TCCCA:T	acceptor_gain	1.0000
12:47711772:CCCA:C	acceptor_gain	1.0000
12:47711772:CCCAC:C	acceptor_gain	1.0000
12:47711773:CCA:C	acceptor_gain	1.0000
12:47711773:CCAC:C	acceptor_gain	1.0000
12:47711774:CA:C	acceptor_gain	1.0000
12:47711774:CAC:C	acceptor_gain	1.0000
12:47711776:C:CA	acceptor_loss	1.0000
12:47711776:C:CC	acceptor_gain	1.0000
12:47711778:G:C	acceptor_gain	1.0000
12:47712512:TCA:T	donor_loss	1.0000
12:47712514:A:AC	donor_gain	1.0000
12:47712514:ACAGG:A	donor_gain	1.0000
12:47712515:C:CC	donor_gain	1.0000
12:47712515:C:G	donor_loss	1.0000
12:47712515:CAGG:C	donor_gain	1.0000
12:47712515:CAGGC:C	donor_gain	1.0000
12:47712618:CTCAC:C	acceptor_gain	1.0000
12:47712620:CAC:C	acceptor_gain	1.0000
12:47713269:TCCCA:T	donor_loss	1.0000
12:47713270:CCCA:C	donor_loss	1.0000
12:47713271:CCACC:C	donor_loss	1.0000
12:47713272:CAC:C	donor_loss	1.0000
12:47713273:ACCT:A	donor_loss	1.0000
12:47713274:C:CT	donor_loss	1.0000

AlphaMissense

2739 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:47713341:A:G	W267R	0.994
12:47713341:A:T	W267R	0.994
12:47711689:G:C	S353R	0.991
12:47711689:G:T	S353R	0.991
12:47711691:T:G	S353R	0.991
12:47712584:A:G	W302R	0.991
12:47712584:A:T	W302R	0.991
12:47713291:A:C	F283L	0.984
12:47713291:A:T	F283L	0.984
12:47713293:A:G	F283L	0.984
12:47711719:C:A	K343N	0.980
12:47711719:C:G	K343N	0.980
12:47713297:A:C	S281R	0.979
12:47713297:A:T	S281R	0.979
12:47713299:T:G	S281R	0.979
12:47712582:C:A	W302C	0.978
12:47712582:C:G	W302C	0.978
12:47711656:G:C	C364W	0.976
12:47711658:A:G	C364R	0.976
12:47713336:A:C	F268L	0.976
12:47713336:A:T	F268L	0.976
12:47713338:A:G	F268L	0.976
12:47716437:A:G	L205P	0.976
12:47711692:G:C	S352R	0.974
12:47711692:G:T	S352R	0.974
12:47711694:T:G	S352R	0.974
12:47713339:C:A	W267C	0.972
12:47713339:C:G	W267C	0.972
12:47711660:A:G	L363P	0.970
12:47713279:G:C	F287L	0.969

dbSNP variants (sampled 300 via entrez): RS1000170129 (12:47717595 T>A,C), RS1000280617 (12:47711880 G>GTAAT), RS1000344496 (12:47724337 G>A,T), RS1000362763 (12:47723987 C>A,T), RS1000404430 (12:47724280 C>T), RS1000432269 (12:47717200 T>C), RS1000966698 (12:47722538 T>C), RS1001013715 (12:47717972 C>A,G,T), RS1001301136 (12:47723068 A>C), RS1001415205 (12:47722770 C>T), RS1001624146 (12:47716703 G>A,T), RS1001634196 (12:47725750 G>A), RS1002507672 (12:47715801 C>T), RS1003030448 (12:47715560 C>G), RS1003502531 (12:47709499 C>G)

Disease associations

OMIM: gene MIM:606720 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_1710	Blood protein levels	4.000000e-10
GCST007611_20	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	7.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol A	increases methylation, decreases methylation, affects cotreatment	1
perfluorooctanoic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Silicon Dioxide	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.