ENDOU

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004521 RNA endonuclease activity	IBA GO_REF:0000033	ACCEPT	Summary: ACCEPT - Core enzymatic function strongly supported by IBA and confirmed experimentally. This phylogenetically-inferred annotation aligns perfectly with the demonstrated molecular function of ENDOU. Reason: PMID:18936097 definitively established ENDOU as an RNA endonuclease with Mn2+-dependent activity that cleaves single-stranded RNA at UU and GU dinucleotide motifs, producing 2',3'-cyclic phosphate termini. This core function is strongly supported by phylogenetic analysis. Supporting Evidence: file:human/ENDOU/ENDOU-deep-research.md See deep research file for comprehensive analysis file:human/ENDOU/ENDOU-deep-research-falcon.md Human ENDOU/PP11 is an uridylate-specific endoribonuclease (an RNase) that binds and cleaves RNA internally (endoribonucleolysis)
GO:0007165 signal transduction	IEA GO_REF:0000108	REMOVE	Summary: REMOVE - This vague IEA annotation likely derives from obsolete protein family classifications. No direct evidence supports ENDOU involvement in signal transduction pathways. The protein functions as an RNA endonuclease that affects gene expression post-transcriptionally, not through signal transduction. Reason: No evidence from PMID:18936097, PMID:37803019, or other references supports signal transduction activity. ENDOU functions as an RNA-degrading enzyme, not a signaling molecule.
GO:0016192 vesicle-mediated transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: MARK_AS_OVER_ANNOTATED - While ENDOU is a secreted protein that passes through the secretory pathway, this annotation implies active participation in vesicle transport mechanisms. The protein is a cargo, not a regulator of vesicle transport. This represents an over-interpretation of the secretory nature of the protein.
GO:0004521 RNA endonuclease activity	IEA GO_REF:0000002	ACCEPT	Summary: ACCEPT - This IEA annotation based on InterPro domain mapping correctly identifies the core molecular function, subsequently confirmed by experimental evidence (PMID:18936097). Reason: PMID:18936097 provided definitive experimental proof of RNA endonuclease activity through biochemical assays showing Mn2+-dependent cleavage of RNA substrates at specific dinucleotide sequences.
GO:0005044 scavenger receptor activity	IEA GO_REF:0000002	REMOVE	Summary: REMOVE - No evidence supports scavenger receptor activity. This erroneous annotation likely stems from early misidentification of ENDOU as a serine protease or confusion with other placental proteins. ENDOU is an RNA endonuclease, not a receptor. Reason: PMID:18936097 definitively disproved receptor activity and established ENDOU as an RNA endonuclease. No binding or signaling assays support scavenger receptor function.
GO:0006955 immune response	IEA GO_REF:0000002	MODIFY	Summary: MODIFY - While too broad, there is strong evidence for ENDOU involvement in B cell tolerance and activation-induced cell death from Poe et al. 2014 (PMID:24344237). Replace with the specific term GO:0002514 (B cell tolerance induction). Note: an earlier draft proposed GO:0006925 (inflammatory cell apoptotic process) as a co-replacement, but B cells are lymphocytes, not inflammatory cells, so that term is inappropriate (PR #685 review feedback). Reason: PMID:24344237 (a mouse study) demonstrated EndoU is a critical regulator of B cell AICD, functioning as a post-transcriptional checkpoint in peripheral B cell tolerance. The broad immune response term should be replaced with the specific term GO:0002514 B cell tolerance induction. This is an ortholog (mouse Endou) finding transferred to the human gene. Proposed replacements: B cell tolerance induction Supporting Evidence: PMID:24344237 defines a new posttranscriptional regulatory pathway that controls B cell AICD, particularly in response to auto-Ag.
GO:0030247 polysaccharide binding	IEA GO_REF:0000002	REMOVE	Summary: REMOVE - No evidence for polysaccharide binding. ENDOU binds RNA (polynucleotide), not polysaccharides. This appears to be a misannotation, possibly from confusion between nucleotides and saccharides.
GO:0003723 RNA binding	IEA GO_REF:0000043	ACCEPT	Summary: ACCEPT - Correct annotation supported by experimental evidence (PMID:18936097). ENDOU binds single-stranded RNA substrates, particularly poly(U) sequences, as part of its endonuclease function. Reason: PMID:18936097 demonstrated RNA binding through electrophoretic mobility shift assays, showing specific binding to RNA substrates with a Kd of approximately 140 nM.
GO:0004518 nuclease activity	IEA GO_REF:0000043	ACCEPT	Summary: ACCEPT - Correct but general parent term. More specific child term "RNA endonuclease activity" is preferred, but this annotation is not incorrect.
GO:0004519 endonuclease activity	IEA GO_REF:0000043	ACCEPT	Summary: ACCEPT - Correct intermediate-level annotation. While "RNA endonuclease activity" is more specific, this parent term accurately describes the molecular function.
GO:0004540 RNA nuclease activity	IEA GO_REF:0000117	ACCEPT	Summary: ACCEPT - Correct annotation. ENDOU is indeed an RNA nuclease, specifically an endoribonuclease. This is a valid parent term of the more specific "RNA endonuclease activity".
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: ACCEPT - Correct localization. ENDOU is a secreted protein with a signal peptide, functioning in the extracellular space as confirmed by multiple studies. Supporting Evidence: file:human/ENDOU/ENDOU-deep-research-falcon.md ENDOU/PP11 was initially isolated as a placenta-derived glycoprotein and is described as highly expressed in the syncytiotrophoblast
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: ACCEPT - Correct high-level annotation. Nucleases are hydrolases that cleave phosphodiester bonds. While very general, this annotation is accurate.
GO:0016829 lyase activity	IEA GO_REF:0000043	ACCEPT	Summary: ACCEPT - UniProt assigns ENDOU both EC 3.1.-.- (hydrolase) and EC 4.6.1.- (phosphorus-oxygen lyase) and carries the Lyase keyword (KW-0456). The 2',3'-cyclic-phosphate-forming intramolecular transesterification (RNase A / EndoU mechanism) is formally classed as a phosphorus-oxygen lyase reaction, so the lyase keyword reflects a deliberate current UniProt classification rather than a stale or erroneous mapping.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MODIFY	Summary: MODIFY - Too general. Should be refined to "manganese ion binding" (GO:0030145) as ENDOU specifically requires Mn2+ for catalytic activity, as demonstrated experimentally. Reason: PMID:18936097 specifically demonstrated manganese-dependent catalytic activity, with Mn2+ being essential for RNA endonuclease function. Proposed replacements: manganese ion binding
GO:0004521 RNA endonuclease activity	IGI PMID:37803019 The endoribonuclease Arlr is required to maintain lipid home...	ACCEPT	Summary: ACCEPT - Strong genetic evidence from Drosophila Arlr (ENDOU ortholog) studies confirming RNA endonuclease activity. This study demonstrated that the EndoU domain is essential for function in lipid metabolism regulation. Reason: PMID:37803019 provided strong genetic evidence using Drosophila Arlr mutants, demonstrating that the EndoU domain is required for normal lipid homeostasis through RNA endonuclease activity. Supporting Evidence: PMID:37803019 indicating that the EndoU-like domain is necessary for Arlr function in LDs
GO:0016441 post-transcriptional gene silencing	IGI PMID:37803019 The endoribonuclease Arlr is required to maintain lipid home...	MODIFY	Summary: MODIFY - GO:0016441 (post-transcriptional gene silencing) is reserved for RNAi / PTGS / miRNA mechanisms operating through the RISC machinery. ENDOU/Arlr does not use the RISC pathway; it directly cleaves target mRNAs via its endoribonuclease activity, producing RNA degradation rather than canonical silencing. Per PR #685 review feedback, replacing with GO:0006401 (RNA catabolic process), already present as a NEW annotation elsewhere in this review. Reason: PMID:37803019 used RIP-seq and functional assays to demonstrate that ENDOU/Arlr specifically binds to and degrades mRNAs of lipolytic genes via direct endonucleolytic cleavage, not RISC-mediated post-transcriptional gene silencing. Proposed replacements: RNA catabolic process Supporting Evidence: PMID:37803019 the signals of Lsd-1, regucalcin, yip2 and CG5162 were all downregulated in the presence of Arlr
GO:0050995 negative regulation of lipid catabolic process	IGI PMID:37803019 The endoribonuclease Arlr is required to maintain lipid home...	ACCEPT	Summary: ACCEPT - Excellent specific annotation based on recent high-quality research. The study clearly demonstrated that ENDOU/Arlr downregulates lipolytic genes (Lsd-1, regucalcin, yip2, CG5162) to maintain lipid homeostasis during aging. This represents a newly discovered core function. Reason: PMID:37803019 provided comprehensive evidence showing ENDOU/Arlr negatively regulates lipid catabolism by degrading specific lipolytic gene mRNAs, with loss-of-function causing accelerated lipid depletion during aging. Supporting Evidence: PMID:37803019 Strikingly, 40 genes related to lipolysis were within the 60 lipid metabolism-related genes, 10 of which we confirmed by qRT-PCR
GO:0003723 RNA binding	IDA PMID:18936097 The tumor marker human placental protein 11 is an endoribonu...	ACCEPT	Summary: ACCEPT - Direct experimental evidence showing ENDOU binds RNA substrates with Kd of 140 nM. Electrophoretic mobility shift assays clearly demonstrated RNA-protein complex formation. Supporting Evidence: PMID:18936097 The estimated K d ′ was equal to 140 n m for PP11
GO:0004521 RNA endonuclease activity	IDA PMID:18936097 The tumor marker human placental protein 11 is an endoribonu...	ACCEPT	Summary: ACCEPT - Definitive experimental proof that ENDOU is an RNA endonuclease. This pivotal study demonstrated Mn2+-dependent cleavage at UU/GU sites producing 2',3'-cyclic phosphate ends, definitively establishing the enzymatic function and correcting the prior misannotation as a serine protease. Supporting Evidence: PMID:18936097 cleaves single stranded RNA in a Mn(2+)-dependent manner at uridylates, to produce molecules with 2',3'-cyclic phosphate ends
GO:0008236 serine-type peptidase activity	IDA NOT PMID:18936097 The tumor marker human placental protein 11 is an endoribonu...	ACCEPT	Summary: PMID:18936097 shows ENDOU lacks serine-type peptidase activity (negative result in chromogenic protease assays) and is instead an RNA endonuclease. Reason: This is a NOT annotation in GOA. PMID:18936097 explicitly reported no detectable serine protease activity, so the negated annotation is appropriate. Supporting Evidence: PMID:18936097 the absence of protease activity in the recombinant His-PP11 that, instead,
GO:0030145 manganese ion binding	TAS PMID:18936097 The tumor marker human placental protein 11 is an endoribonu...	ACCEPT	Summary: ACCEPT - Correct and specific annotation. The study demonstrated that ENDOU activity is Mn2+-dependent, with manganese ions essential for the catalytic mechanism. Supporting Evidence: PMID:18936097 behaves as a Mn 2+ -dependent, U-specific endoribonuclease file:human/ENDOU/ENDOU-deep-research-falcon.md Biochemical assays showed ENDOU is uridylate-directed (cleaves at/near uridylate residues) and is Mn²⁺-dependent under the tested in vitro conditions
GO:0005886 plasma membrane	TAS PMID:1710108 Homology of placental protein 11 and pea seed albumin 2 with...	REMOVE	Summary: REMOVE - ENDOU is a secreted protein, not a membrane-bound protein. While it may transiently associate with membranes during secretion, there is no evidence for stable plasma membrane localization. The protein lacks transmembrane domains. Supporting Evidence: PMID:1710108 Homology of placental protein 11 and pea seed albumin 2 with vitronectin.
GO:0008083 growth factor activity	NAS PMID:1710108 Homology of placental protein 11 and pea seed albumin 2 with...	REMOVE	Summary: REMOVE - No evidence supports growth factor activity. This early annotation was based on sequence similarity to vitronectin, but ENDOU functions as an RNA endonuclease, not a growth factor. This represents an outdated misannotation from before the true function was discovered. Supporting Evidence: PMID:1710108 Homology of placental protein 11 and pea seed albumin 2 with vitronectin.
GO:0005576 extracellular region	TAS PMID:1710108 Homology of placental protein 11 and pea seed albumin 2 with...	ACCEPT	Summary: ACCEPT - Correct localization. ENDOU is indeed a secreted protein found in the extracellular space, consistent with its signal peptide and secretory pathway trafficking. Supporting Evidence: PMID:1710108 Computer-assisted data base searches revealed the presence of a single somatomedin B domain in the recently cloned placental protein 11
GO:0005737 cytoplasm	TAS PMID:2350438 Cloning and expression of a cDNA encoding human placental pr...	ACCEPT	Summary: ACCEPT - ENDOU is present in the cytoplasm of secretory cells prior to secretion. Immunohistochemistry shows cytoplasmic localization in syncytiotrophoblasts and other producing cells. Supporting Evidence: PMID:2350438 higher-molecular-weight form of approximately 42 kD in the cytoplasm file:human/ENDOU/ENDOU-deep-research-falcon.md Prior localization work cited by Laneve et al. reported PP11 to be exclusively localized in the cytoplasm of syncytiotrophoblast
GO:0005737 cytoplasm	IDA PMID:6755403 Immunohistochemical detection of pregnancy-specific protein ...	ACCEPT	Summary: ACCEPT - Immunohistochemical evidence for cytoplasmic localization in ovarian carcinoma cells. Consistent with ENDOU being synthesized in the cytoplasm before secretion. Supporting Evidence: PMID:6755403 These proteins could be detected in the cytoplasm of some malignant cells
GO:0006508 proteolysis	IDA PMID:2350438 Cloning and expression of a cDNA encoding human placental pr...	REMOVE	Summary: REMOVE - This annotation is based on the original misidentification of ENDOU as a serine protease. Later studies (PMID:18936097) definitively proved ENDOU has no protease activity. This outdated annotation must be removed. Supporting Evidence: PMID:2350438 Cloning and expression of a cDNA encoding human placental protein 11, a putative serine protease with diagnostic significance as a tumor marker.
GO:0007565 female pregnancy	IEP PMID:2350438 Cloning and expression of a cDNA encoding human placental pr...	KEEP AS NON CORE	Summary: KEEP_AS_NON_CORE - ENDOU is highly expressed in placental syncytiotrophoblast during pregnancy. While this reflects tissue-specific expression rather than a core molecular function, the association with pregnancy is valid for this placental protein. Supporting Evidence: PMID:2350438 Cloning and expression of a cDNA encoding human placental protein 11, a putative serine protease with diagnostic significance as a tumor marker.
GO:0008236 serine-type peptidase activity	IDA PMID:2350438 Cloning and expression of a cDNA encoding human placental pr...	REMOVE	Summary: REMOVE - Based on incorrect initial characterization. The 1990 paper assumed protease activity based on sequence similarity, but this was definitively disproven by PMID:18936097, which showed no protease activity and established ENDOU as an RNA endonuclease. Supporting Evidence: PMID:2350438 Cloning and expression of a cDNA encoding human placental protein 11, a putative serine protease with diagnostic significance as a tumor marker.
GO:0005615 extracellular space	TAS PMID:2350438 Cloning and expression of a cDNA encoding human placental pr...	ACCEPT	Summary: ACCEPT - Correct annotation. ENDOU is a secreted protein found in the extracellular space, consistent with its signal peptide and lack of transmembrane domains. Supporting Evidence: PMID:2350438 369 amino acids, including a typical hydrophobic signal sequence of 18 amino acids
GO:0006401 RNA catabolic process	IEA PMID:18936097 The tumor marker human placental protein 11 is an endoribonu...	NEW	Summary: ENDOU cleaves single-stranded RNA as an endoribonuclease Reason: ENDOU is a uridylate-specific endoribonuclease that cleaves single-stranded RNAs at UU and GU dinucleotides, releasing products with 2',3'-cyclic phosphates. This RNA cleavage activity directly participates in RNA catabolism. Supporting Evidence: PMID:18936097 Here we show that the bacterially expressed human PP11 displays RNA binding capability and cleaves single stranded RNA in a Mn(2+)-dependent manner at uridylates, to produce molecules with 2',3'-cyclic phosphate ends.
GO:0034976 response to endoplasmic reticulum stress	IDA PMID:33511665 Poly(U)-specific endoribonuclease ENDOU promotes translation...	NEW	Summary: NEW - ENDOU cleaves inhibitory uORF in CHOP mRNA to promote CHOP translation during ER stress. The 2021 study by Lee et al. demonstrated that ENDOU-mediated cleavage is a critical regulatory switch for the stress response, enabling IRES-dependent translation of CHOP. Reason: PMID:33511665 showed that ENDOU cleaves the CHOP mRNA uORF at position 80G-81U, converting the mRNA to an IRES-containing form that bypasses translational repression during ER stress. This represents a novel post-transcriptional mechanism for regulating stress-induced gene expression. Supporting Evidence: file:human/ENDOU/ENDOU-deep-research-openai.md ENDOU cuts the CHOP uORF at a specific site (between a G and a U nucleotide in the uORF sequence), generating a truncated mRNA segment. This cleavage allows ribosomes to bypass the uORF and re-initiate at the main coding sequence PMID:33511665 We also found that Endouc/ENDOU-1 binds and cleaves the huORFchop transcript at position 80G-81U, which induces CHOP translation independently of phosphorylated eIF2α
GO:0045727 positive regulation of translation	IDA PMID:33511665 Poly(U)-specific endoribonuclease ENDOU promotes translation...	NEW	Summary: NEW - ENDOU positively regulates translation of target mRNAs by cleaving inhibitory uORF elements. The CHOP mRNA study demonstrated that ENDOU-mediated cleavage facilitates ribosomal bypass of the inhibitory huORFchop element, enhancing CHOP translation. The directional (positive) term GO:0045727 is preferred over the general GO:0006417 because the demonstrated effect is an increase in translation. Reason: Lee et al. (PMID:33511665) established that ENDOU positively regulates CHOP translation by cleaving the uORF element, resulting in increased CHOP protein levels (shown in human HEK293T/HeLa cells and zebrafish). This represents a specific role in positive translational regulation distinct from general RNA degradation. Supporting Evidence: PMID:33511665 facilitates ribosomal bypass of an inhibitory huORFchop to enhance CHOP mRNA translation PMID:33511665 overexpression of Endouc in HEK293T and HeLa cells increased CHOP expression
GO:0043065 positive regulation of apoptotic process	IDA PMID:24344237 EndoU is a novel regulator of AICD during peripheral B cell ...	NEW	Summary: NEW - EndoU positively regulates apoptosis (activation-induced cell death, AICD) of autoreactive B cells by downregulating c-Myc. Poe et al. 2014 (a mouse study; CD22-/- B6 and IgTgsHEL models) showed that EndoU gene disruption prevents AICD, identifying EndoU as a positive regulator of B cell apoptosis. The directional term GO:0043065 is preferred over the bare GO:0006915 because EndoU promotes, rather than merely participates in, apoptosis. Reason: PMID:24344237 (mouse) showed that EndoU-deficient B cells fail to undergo AICD due to abnormally elevated c-Myc levels; EndoU gene disruption prevents AICD and normalizes c-Myc. By downregulating c-Myc post-transcriptionally, EndoU promotes apoptosis and contributes to peripheral B cell tolerance. This is an ortholog (mouse Endou) finding transferred to the human gene. Supporting Evidence: PMID:24344237 EndoU gene disruption prevents AICD and normalizes c-Myc file:human/ENDOU/ENDOU-deep-research-openai.md EndoU is upregulated in B cells undergoing AICD. When EndoU was knocked out or disrupted, these B cells failed to undergo cell death. EndoU activity appears to help downregulate c-Myc post-transcriptionally
GO:0005509 calcium ion binding	IDA PMID:40169637 Molecular basis for the calcium-dependent activation of the ...	NEW	Summary: NEW - ENDOU binds calcium ions at an allosteric site that activates the enzyme. The 2025 study by Malard et al. solved the crystal structure showing Ca2+ binding triggers conformational changes that align the catalytic residues for RNA cleavage. Reason: PMID:40169637 demonstrated through structural biology that calcium binding at a site remote from the catalytic triad induces allosteric activation of ENDOU, providing a molecular switch for controlled RNase activity in response to cellular calcium signaling. Supporting Evidence: file:human/ENDOU/ENDOU-deep-research-openai.md calcium binding triggers an allosteric conformational change that activates the enzyme. The Ca2+ ion binds at a site remote from the catalytic triad, bridging parts of the N-terminal extension and the core PMID:40169637 We determine the crystal structure of EndoU bound to calcium and find that calcium binding remote from the catalytic triad triggers water-mediated intramolecular signaling and structural changes, activating the enzyme through allostery

Gene Description

Existing Annotations Review

Core Functions

Cleaves single-stranded RNA at UU and GU dinucleotides through divalent-cation-dependent endonuclease activity (Mn2+ in early in vitro assays; Ca2+ for the human/mouse enzyme)

Degrades lipolytic gene mRNAs to suppress lipid catabolism and maintain lipid storage

Produces 2',3'-cyclic phosphate termini via His-His-Lys catalytic triad mechanism

Binds RNA substrates with preference for uridine-rich sequences

Binds divalent metal cofactor required for catalysis; manganese was reported in early in vitro work on bacterially expressed protein, while structural studies of the human/mouse enzyme show specific activation by calcium

Cleaves CHOP mRNA uORF to promote translation during ER stress, enabling IRES-mediated translation of the stress-induced transcription factor

Regulates B cell activation-induced cell death by targeting c-Myc mRNA, contributing to peripheral B cell tolerance

Calcium-dependent activation via allosteric conformational change enables regulated RNA cleavage under specific cellular conditions

References

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Deep Research Report: ENDOU (human)

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