UPF3A

UniProt ID: Q9H1J1
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

UPF3A (Regulator of nonsense transcripts 3A; hUpf3p/hUPF3L) is a nonsense-mediated mRNA decay (NMD) factor and the paralog of UPF3B. It is a nuclear/cytoplasmic shuttling protein that associates with the exon-junction complex (EJC) deposited upstream of exon-exon junctions on spliced mRNA and acts as a molecular adaptor bridging the EJC to the core NMD machinery, binding UPF2 (and RBM8A/EJC) and helping assemble the UPF1-UPF2-UPF3 surveillance complex that licenses decay of premature-termination-codon-containing mRNAs. UPF3A is only marginally active in promoting NMD compared with UPF3B; because the two paralogs compete for the same MIF4G-III surface of UPF2, UPF3A can act as an NMD antagonist/repressor by sequestering UPF2, and in many tissues UPF3A is itself cleared but is stabilized by binding UPF2 when functional UPF3B is absent. UPF3A also binds spliced mRNA and weakly stimulates translation in vitro, and has been reported to bind telomeric-repeat (TERRA) RNA/DNA in the context of telomere RNA surveillance. Through these activities UPF3A contributes to the magnitude and substrate selectivity of NMD and to paralog-buffering of the NMD pathway during development.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: UPF3A shuttles between nucleus and cytoplasm and is active in the cytoplasm, where the UPF1-UPF2-UPF3 surveillance complex assembles; well supported.
Reason: Cytoplasmic activity is consistent with the NMD adaptor role and experimental localization, and with the phylogenetic inference.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Recruits UPF2 at the cytoplasmic side
GO:0042162 telomeric repeat DNA binding
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetically inferred telomeric-repeat binding, corroborated by direct evidence that UPF3A associates with telomeric-repeat (TERRA) nucleic acid in telomere RNA surveillance. A specialized, non-core activity.
Reason: Telomeric-repeat binding is experimentally reported (TERRA context) but peripheral to UPF3A's core NMD adaptor function.
Supporting Evidence:
PMID:17916692
telomeres are transcribed into telomeric repeat-containing RNA (TERRA).
GO:0045727 positive regulation of translation
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: UPF3A weakly stimulates translation in vitro; the effect is modest and secondary to its NMD role.
Reason: Translation stimulation is reported but described as weak/in vitro; it is a minor, non-core activity relative to the NMD adaptor function.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
weakly stimulates
GO:0003676 nucleic acid binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro-based nucleic acid binding (UPF3A has an RRM-like fold and binds RNA). The specific mRNA binding term is more informative.
Reason: Correct but general; the specific GO:0003729 (mRNA binding) better captures UPF3A's RNA-binding activity.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Binds spliced mRNA
GO:0005634 nucleus
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic nuclear localization, consistent with UPF3A's role in associating with the nuclear EJC and shuttling to the cytoplasm.
Reason: Nuclear localization is supported experimentally (UPF3A associates with the nuclear EJC); agrees with NAS nucleus annotation.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
associating with the nuclear exon
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic cytoplasmic localization, consistent with UPF3A shuttling and recruiting UPF2 at the cytoplasmic side of the nuclear envelope.
Reason: Agrees with experimental/NAS cytoplasm localization and the NMD adaptor role.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Recruits UPF2 at the cytoplasmic side
GO:0035145 exon-exon junction complex
IEA
GO_REF:0000117 		ACCEPT
Summary: UPF3A associates with the exon-junction complex (EJC), serving as the link between the EJC core and the NMD machinery; a core cellular component.
Reason: EJC association is directly documented (IDA/TAS) and is central to UPF3A's adaptor function.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
serving as link between the EJC core and NMD
GO:0045727 positive regulation of translation
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: ARBA-based electronic annotation of translation stimulation; UPF3A weakly stimulates translation in vitro.
Reason: Reported as weak/in vitro; a minor, non-core activity relative to the NMD adaptor role.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
weakly stimulates
GO:0005515 protein binding
IPI
PMID:11163187
Human Upf proteins target an mRNA for nonsense-mediated deca... 		KEEP AS NON CORE
Summary: IntAct interactions with UPF1 (Q92900) and UPF2 (Q9HAU5), the core NMD partners that UPF3A bridges. The bare protein binding term is uninformative.
Reason: Records the functionally central UPF1/UPF2 interactions, but bare protein binding is uninformative; the adaptor role is captured by NMD/EJC terms.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q92900: UPF1
GO:0005515 protein binding
IPI
PMID:11546873
Role of the nonsense-mediated decay factor hUpf3 in the spli... 		KEEP AS NON CORE
Summary: IntAct interaction with RBM8A/Y14 (Q9Y5S9), an EJC core component. The bare protein binding term is uninformative.
Reason: Records a real EJC interaction but bare protein binding is uninformative and not core.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q9Y5S9: RBM8A
GO:0005515 protein binding
IPI
PMID:11546874
Communication of the position of exon-exon junctions to the ... 		KEEP AS NON CORE
Summary: IntAct interaction with RBM8A/Y14 (Q9Y5S9), an EJC core component. The bare protein binding term is uninformative.
Reason: Records a real EJC interaction but bare protein binding is uninformative and not core.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q9Y5S9: RBM8A
GO:0005515 protein binding
IPI
PMID:12417715
Identification of a human decapping complex associated with ... 		KEEP AS NON CORE
Summary: IntAct interaction with UPF1 (Q92900). The bare protein binding term is uninformative.
Reason: Records the functionally relevant UPF1 interaction but bare protein binding is uninformative and not core.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q92900: UPF1
GO:0005515 protein binding
IPI
PMID:19503078
A UPF3-mediated regulatory switch that maintains RNA surveil... 		KEEP AS NON CORE
Summary: IntAct interactions with UPF3B (Q9BZI7-2) and UPF2 (Q9HAU5). The bare protein binding term is uninformative.
Reason: Records the paralog UPF3B and UPF2 interactions central to NMD competition, but bare protein binding is uninformative and not core.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q9BZI7-2: UPF3B
GO:0005515 protein binding
IPI
PMID:20479275
Insights into the recruitment of the NMD machinery from the ... 		KEEP AS NON CORE
Summary: IntAct interaction with UPF2 (Q9HAU5). The bare protein binding term is uninformative.
Reason: Records the functionally central UPF2 interaction but bare protein binding is uninformative and not core.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q9HAU5: UPF2
GO:0043005 neuron projection
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Ortholog-transferred (mouse) neuron-projection localization. There is no direct human evidence; UPF3A is a broadly expressed nucleocytoplasmic NMD factor.
Reason: Localization transferred from the mouse ortholog without direct human support; not a core or well-established compartment for UPF3A.
Supporting Evidence:
file:human/UPF3A/UPF3A-goa.tsv
ensembl:ENSMUSP00000037354
GO:2000623 negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
IEA
GO_REF:0000107 		ACCEPT
Summary: UPF3A can act as an NMD repressor/antagonist by sequestering UPF2, dampening NMD; ortholog-transferred annotation corroborated by experimental evidence (PMID:27040500).
Reason: UPF3A's NMD-antagonist role (UPF2 sequestration) is experimentally established and is a genuine, distinctive function; consistent with the ortholog transfer.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
only marginally active in NMD
GO:0071025 RNA surveillance
NAS
PMID:31131562
Nonsense-mediated mRNA decay: The challenge of telling right... 		ACCEPT
Summary: UPF3A participates in RNA surveillance (NMD), the broad quality-control process that distinguishes aberrant from normal mRNAs.
Reason: RNA surveillance is the overarching process to which UPF3A's NMD adaptor function contributes; well supported.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Involved in nonsense-mediated decay (NMD) of mRNAs containing
GO:0170010 nonsense-mediated decay complex
NAS
PMID:35640974
Structures of nonsense-mediated mRNA decay factors UPF3B and... 		ACCEPT
Summary: UPF3A is a component of the NMD (UPF1-UPF2-UPF3 surveillance) complex, the core cellular-component context for its adaptor function.
Reason: UPF3A's membership in the UPF surveillance/NMD complex is directly supported (including structures of UPF3A-UPF2); a core cellular component.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
UPF1-UPF2-UPF3 surveillance
GO:2000623 negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
NAS
PMID:31131562
Nonsense-mediated mRNA decay: The challenge of telling right... 		ACCEPT
Summary: UPF3A negatively regulates NMD (antagonist/repressor) by competing for UPF2; a genuine, distinctive function.
Reason: Well supported by the literature on UPF3A as an NMD antagonist (UPF2 sequestration); consistent with UPF3A being only marginally active in promoting decay.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
only marginally active in NMD
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct immunofluorescence (HPA) nucleoplasmic localization, consistent with UPF3A's nuclear EJC association.
Reason: Agrees with the nuclear localization expected for an EJC-associated NMD factor.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
associating with the nuclear exon
GO:0003729 mRNA binding
IDA
PMID:11163187
Human Upf proteins target an mRNA for nonsense-mediated deca... 		ACCEPT
Summary: UPF3A binds spliced mRNA upstream of exon-exon junctions; a core molecular function underlying its EJC/NMD adaptor role.
Reason: Directly demonstrated mRNA binding; an informative, core molecular function.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Binds spliced mRNA
GO:0140311 protein sequestering activity
IMP
PMID:27040500
The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsen... 		ACCEPT
Summary: UPF3A sequesters UPF2, thereby antagonizing/repressing NMD; this protein-sequestering activity is the molecular basis of its NMD-repressor function.
Reason: Experimentally supported (UPF3A buffers NMD by sequestering UPF2); a genuine, distinctive molecular function for this paralog.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
only marginally active in NMD
GO:2000623 negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
IPI
PMID:27040500
The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsen... 		ACCEPT
Summary: UPF3A negatively regulates NMD via its interaction with UPF2 (Q9HAU5), sequestering it from the active NMD machinery.
Reason: Directly supported; the UPF2 interaction underlies UPF3A's NMD-antagonist role.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q9HAU5: UPF2
GO:0005515 protein binding
IPI
PMID:25220460
The RNA helicase DHX34 activates NMD by promoting a transiti... 		KEEP AS NON CORE
Summary: IntAct interaction with the RNA helicase DHX34 (Q14147), which promotes the surveillance-to-decay transition in NMD. The bare protein binding term is uninformative.
Reason: Records a functionally relevant DHX34 interaction but bare protein binding is uninformative and not core.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Interacts with DHX34
GO:0035145 exon-exon junction complex
TAS
PMID:11546873
Role of the nonsense-mediated decay factor hUpf3 in the spli... 		ACCEPT
Summary: UPF3A is part of the exon-junction complex; a core cellular component for its adaptor function.
Reason: EJC membership is well supported (TAS and IDA); central to UPF3A's role.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
serving as link between the EJC core and NMD
GO:0035145 exon-exon junction complex
IDA
PMID:16601204
Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA dec... 		ACCEPT
Summary: Direct evidence that UPF3A is part of the exon-junction complex; a core cellular component.
Reason: Directly demonstrated EJC association; central to UPF3A's adaptor function.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
serving as link between the EJC core and NMD
GO:0042162 telomeric repeat DNA binding
IDA
PMID:17916692
Telomeric repeat containing RNA and RNA surveillance factors... 		KEEP AS NON CORE
Summary: Direct evidence that UPF3A associates with telomeric-repeat (TERRA) nucleic acid in telomere RNA surveillance; a specialized, non-core activity.
Reason: Experimentally reported in the TERRA/telomere context, but peripheral to UPF3A's core NMD adaptor function.
Supporting Evidence:
PMID:17916692
telomeres are transcribed into telomeric repeat-containing RNA (TERRA).
GO:0005829 cytosol
TAS
Reactome:R-HSA-927813 		ACCEPT
Summary: Reactome curated cytosolic localization (NMD pathway), consistent with the cytoplasmic phase of NMD where UPF3A acts.
Reason: Consistent with UPF3A's cytoplasmic NMD-adaptor activity.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Recruits UPF2 at the cytoplasmic side
GO:0005829 cytosol
TAS
Reactome:R-HSA-927832 		ACCEPT
Summary: Reactome curated cytosolic localization (NMD pathway), redundant with the other cytosol annotations.
Reason: Consistent with UPF3A's cytoplasmic NMD activity.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Recruits UPF2 at the cytoplasmic side
GO:0005829 cytosol
TAS
Reactome:R-HSA-927836 		ACCEPT
Summary: Reactome curated cytosolic localization (NMD pathway).
Reason: Consistent with UPF3A's cytoplasmic NMD activity.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Recruits UPF2 at the cytoplasmic side
GO:0005829 cytosol
TAS
Reactome:R-HSA-927889 		ACCEPT
Summary: Reactome curated cytosolic localization (NMD pathway).
Reason: Consistent with UPF3A's cytoplasmic NMD activity.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Recruits UPF2 at the cytoplasmic side
GO:0000184 nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
IDA NOT
PMID:16601204
Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA dec... 		ACCEPT
Summary: NOT annotation. In the assay of PMID:16601204, UPF3A did not function in (canonical) NMD, consistent with UPF3A being only marginally active in promoting decay compared with UPF3B. This negation is an important, deliberate curation.
Reason: The negated annotation correctly records that UPF3A is largely inactive in canonical NMD (in contrast to UPF3B), aligning with the UniProt statement that UPF3A is only marginally active in NMD and with its NMD-antagonist role.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
only marginally active in NMD
GO:0045727 positive regulation of translation
IDA
PMID:16601204
Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA dec... 		KEEP AS NON CORE
Summary: UPF3A weakly stimulates translation in vitro; a minor activity reported alongside its (limited) NMD role.
Reason: Reported as weak/in vitro; a minor, non-core activity relative to the NMD adaptor function.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
weakly stimulates
GO:0005515 protein binding
IPI
PMID:14636577
Phosphorylation of hUPF1 induces formation of mRNA surveilla... 		KEEP AS NON CORE
Summary: IntAct interactions with UPF-pathway partners including UPF2 (Q9HAU5) and a SMG/UPF-complex component (Q92540). The bare protein binding term is uninformative.
Reason: Records interactions relevant to UPF surveillance-complex formation, but bare protein binding is uninformative and not core.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Q9H1J1; Q9HAU5: UPF2
GO:0005634 nucleus
NAS
PMID:11163187
Human Upf proteins target an mRNA for nonsense-mediated deca... 		ACCEPT
Summary: Nuclear localization (author statement), consistent with UPF3A's nuclear EJC association and nucleocytoplasmic shuttling.
Reason: Consistent with experimental evidence for nuclear localization of UPF3A.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
SUBCELLULAR LOCATION: Nucleus
GO:0005737 cytoplasm
NAS
PMID:11163187
Human Upf proteins target an mRNA for nonsense-mediated deca... 		ACCEPT
Summary: Cytoplasmic localization (author statement), consistent with UPF3A shuttling and the cytoplasmic phase of NMD.
Reason: Consistent with experimental evidence and the NMD adaptor role.
Supporting Evidence:
file:human/UPF3A/UPF3A-uniprot.txt
Recruits UPF2 at the cytoplasmic side

Core Functions

Nonsense-mediated mRNA decay (NMD) adaptor that associates with the exon-junction complex on spliced mRNA and bridges it to the core NMD machinery, binding UPF2 (and RBM8A/EJC) and helping assemble the UPF1-UPF2-UPF3 surveillance complex that targets premature-termination-codon-containing mRNAs.

Molecular Function:
mRNA binding
In Complex:
nonsense-mediated decay complex
Supporting Evidence:
  • file:human/UPF3A/UPF3A-uniprot.txt
    serving as link between the EJC core and NMD
  • file:human/UPF3A/UPF3A-uniprot.txt
    Binds spliced mRNA

NMD modulator/antagonist; UPF3A is only marginally active in promoting decay and competes with UPF3B for UPF2, sequestering UPF2 to repress/buffer NMD, contributing to paralog-dependent control of NMD magnitude.

Molecular Function:
protein sequestering activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/UPF3A/UPF3A-uniprot.txt
    only marginally active in NMD
  • PMID:35640974
    protect itself from degradation by interaction with UPF2

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
PMID:11163187
Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon.
  • UPF3A binds spliced mRNA, associates with the EJC and the UPF1/UPF2 machinery, and links the EJC to NMD.
PMID:11546873
Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon-exon junction complex.
  • hUpf3/UPF3A is a component of the splicing-dependent exon-exon junction complex (EJC).
PMID:11546874
Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1.
PMID:12417715
Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay.
PMID:14636577
Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7.
PMID:16601204
Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation.
  • UPF3A is part of the EJC and, in contrast to UPF3B, is largely inactive in canonical NMD; it weakly stimulates translation.
PMID:17916692
Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends.
  • NMD/RNA-surveillance factors including UPF3A associate with telomeric-repeat-containing RNA (TERRA) at chromosome ends.
PMID:19503078
A UPF3-mediated regulatory switch that maintains RNA surveillance.
PMID:20479275
Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex.
PMID:25220460
The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex.
  • UPF3A interacts (RNA-independently) with the RNA helicase DHX34, which promotes the surveillance-to-decay-complex transition in NMD.
PMID:27040500
The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay.
  • UPF3A acts as an NMD antagonist/repressor that sequesters UPF2, buffering NMD; UPF3A and UPF3B have antagonistic roles in governing NMD during development.
PMID:31131562
Nonsense-mediated mRNA decay: The challenge of telling right from wrong in a complex transcriptome.
  • UPF3A participates in NMD/RNA surveillance and can both contribute to and repress NMD depending on context.
PMID:35640974
Structures of nonsense-mediated mRNA decay factors UPF3B and UPF3A in complex with UPF2 reveal molecular basis for competitive binding and for neurodevelopmental disorder-causing mutation.
  • Crystal structures show UPF3A and UPF3B bind the same MIF4G-III domain of UPF2 competitively; UPF3A can protect itself from degradation by binding UPF2 when UPF3B is absent.
Reactome:R-HSA-927813
Reactome NMD pathway (cytosol localization of UPF3A)
Reactome:R-HSA-927832
Reactome NMD pathway (cytosol localization of UPF3A)
Reactome:R-HSA-927836
Reactome NMD pathway (cytosol localization of UPF3A)
Reactome:R-HSA-927889
Reactome NMD pathway (cytosol localization of UPF3A)

Suggested Questions for Experts

Q: Under what physiological/developmental conditions does UPF3A act as an NMD activator (bridging UPF2/EJC) versus an NMD repressor (sequestering UPF2), and what controls the switch?

Q: How does UPF3A protein stability (its clearance in many tissues and stabilization by UPF2 when UPF3B is absent) tune the magnitude of NMD in different cell types?

Q: Are UPF3A's reported telomeric-repeat/TERRA-binding and weak translation-stimulation activities physiologically significant, or incidental to its RRM-based RNA binding?

Suggested Experiments

Experiment: Degron-controlled UPF3A depletion/restoration (with and without UPF3B) combined with transcriptome-wide NMD-substrate profiling to quantify UPF3A's activator versus repressor contributions across substrate classes.

Experiment: Structure-guided UPF2-binding mutants of UPF3A that disrupt the competitive MIF4G-III interaction, tested for NMD repression, UPF3A stability, and UPF3B buffering.

Experiment: Comparative CLIP-seq of UPF3A and UPF3B to define their mRNA/EJC binding landscapes and whether UPF3A binding marks transcripts protected from decay.

📚 Additional Documentation

Notes

(UPF3A-notes.md)

UPF3A (Q9H1J1) research notes

Summary

UPF3A (Regulator of nonsense transcripts 3A; hUpf3p/hUPF3L) is a nonsense-mediated mRNA decay (NMD) factor and the paralog of UPF3B. It is a nuclear/cytoplasmic shuttling protein that associates with the exon-junction complex (EJC) deposited upstream of exon-exon junctions on spliced mRNA and acts as a molecular adaptor bridging the EJC to the core NMD machinery, binding UPF2 (and RBM8A/EJC) and helping assemble the UPF1-UPF2-UPF3 surveillance complex that licenses decay of premature-termination-codon-containing mRNAs. UPF3A is only marginally active in promoting NMD compared with UPF3B; because the two paralogs compete for the same MIF4G-III surface of UPF2, UPF3A can act as an NMD antagonist/repressor by sequestering UPF2, and in many tissues UPF3A is itself cleared but is stabilized by binding UPF2 when functional UPF3B is absent. UPF3A also binds spliced mRNA and weakly stimulates translation in vitro, and has been reported to bind telomeric-repeat (TERRA) RNA/DNA in the context of telomere RNA surveillance. Through these activities UPF3A contributes to the magnitude and substrate selectivity of NMD and to paralog-buffering of the NMD pathway during development.

Core functions (from review)

  • GO:0003729 mRNA binding — Nonsense-mediated mRNA decay (NMD) adaptor that associates with the exon-junction complex on spliced mRNA and bridges it to the core NMD machinery, binding UPF2 (and RBM8A/EJC) and helping assemble the UPF1-UPF2-UPF3 surveillance complex that targets premature-termination-codon-containing mRNAs.
  • GO:0140311 protein sequestering activity — NMD modulator/antagonist; UPF3A is only marginally active in promoting decay and competes with UPF3B for UPF2, sequestering UPF2 to repress/buffer NMD, contributing to paralog-dependent control of NMD magnitude.

Provenance

Research and verbatim supporting quotes are recorded inline in UPF3A-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(UPF3A-pn-notes.md)

UPF3A PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9H1J1
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: UPF3A (Regulator of nonsense transcripts 3A; hUpf3p/hUPF3L) is a nonsense-mediated mRNA decay (NMD) factor and the paralog of UPF3B. It is a nuclear/cytoplasmic shuttling protein that associates with the exon-junction complex (EJC) deposited upstream of exon-exon junctions on spliced mRNA and acts as a molecular adaptor bridging the EJC to the core NMD machinery, binding UPF2 (and RBM8A/EJC) and helping assemble the UPF1-UPF2-UPF3 surveillance complex that licenses decay of premature-termination-codon-containing mRNAs. UPF3A is only marginally active in promoting NMD compared with UPF3B; because the two paralogs compete for the same MIF4G-III surface of UPF2, UPF3A can act as an NMD antagonist/repressor by sequestering UPF2, and in many tissues UPF3A is itself cleared but is stabilized by binding UPF2 when functional UPF3B is absent. UPF3A also binds spliced mRNA and weakly stimulates translation in vitro, and has been reported to bind telomeric-repeat (TERRA) RNA/DNA in the context of telomere RNA surveillance. Through these activities UPF3A contributes to the magnitude and substrate selectivity of NMD and to paralog-buffering of the NMD pathway during development.
  • Existing/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 14; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Gene-level consistent and notably careful on directionality: deep-research/notes and review YAML agree UPF3A is the partial NMD ANTAGONIST of UPF3B — only marginally active in canonical NMD, competes with UPF3B for the UPF2 MIF4G-III surface, sequesters UPF2 to repress/buffer NMD. The review encodes this with a NEGATED GO:0000184 (NMD, NOT, IDA PMID:16601204, ACCEPT) and an ACCEPTed GO:2000623 (negative regulation of NMD), plus core_function GO:0140311 protein sequestering activity. This antagonist directionality is the opposite of the simple "termination factor" the PN node implies — a real framing mismatch.
  • PN story / NEW pressure: PN groups UPF3A with the active termination/NMD factors and projects GO:0006415 as new_to_goa. This both (a) over-reaches as with the other UPF genes (UPF3A is not a peptide-release factor), and (b) ignores UPF3A's antagonist/negative-regulation directionality already captured by GO:2000623. No NEW term needed; the negative-regulation and sequestering story is already annotated.
  • Evidence alignment: PN row carries no reference titles; review cites PMID:16601204 (UPF3A inactive in canonical NMD), PMID:35640974 (UPF2-dependent stabilization), PMID:14636577 (UPF2/EJC interactions). No competing PN citations.
  • Verdict: Consistent gene biology with correct antagonist directionality in the YAML; PN group→GO:0006415 over-reaches AND mis-directs (UPF3A is an NMD repressor — GO:2000623 — not a termination/decay driver).

Full Consistency Review

  • UniProt: Q9H1J1 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Translation termination|Modulation of termination ; PN-node mapping: type no_mapping; group mapped, ok_for_propagation → GO:0006415 translational termination; class/branch context_only, too_broad. Projected: GO:0006415 (goa_status=new_to_goa).
  • Consistency: Gene-level consistent and notably careful on directionality: deep-research/notes and review YAML agree UPF3A is the partial NMD ANTAGONIST of UPF3B — only marginally active in canonical NMD, competes with UPF3B for the UPF2 MIF4G-III surface, sequesters UPF2 to repress/buffer NMD. The review encodes this with a NEGATED GO:0000184 (NMD, NOT, IDA PMID:16601204, ACCEPT) and an ACCEPTed GO:2000623 (negative regulation of NMD), plus core_function GO:0140311 protein sequestering activity. This antagonist directionality is the opposite of the simple "termination factor" the PN node implies — a real framing mismatch.
  • PN story / NEW pressure: PN groups UPF3A with the active termination/NMD factors and projects GO:0006415 as new_to_goa. This both (a) over-reaches as with the other UPF genes (UPF3A is not a peptide-release factor), and (b) ignores UPF3A's antagonist/negative-regulation directionality already captured by GO:2000623. No NEW term needed; the negative-regulation and sequestering story is already annotated.
  • Mapping strategy: GROUP→GO:0006415 is wrong for UPF3A on two counts: wrong process (peptide release) and wrong direction (UPF3A dampens, not drives, decay). Projecting a positive translation-termination/NMD-adjacent term onto a partial antagonist is a directionality error the reviewers explicitly guarded against (negated GO:0000184). Type-level no_mapping should govern.
  • Evidence alignment: PN row carries no reference titles; review cites PMID:16601204 (UPF3A inactive in canonical NMD), PMID:35640974 (UPF2-dependent stabilization), PMID:14636577 (UPF2/EJC interactions). No competing PN citations.
  • Verdict: Consistent gene biology with correct antagonist directionality in the YAML; PN group→GO:0006415 over-reaches AND mis-directs (UPF3A is an NMD repressor — GO:2000623 — not a termination/decay driver).

Recommended edits: [MAP] do NOT project GO:0006415 (translational termination) onto UPF3A; UPF3A is a partial NMD antagonist (negated GO:0000184; GO:2000623 negative regulation of NMD; GO:0140311 sequestering). The type-level no_mapping should win, and any node-level frame must respect its negative/antagonist directionality.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/UPF3A/UPF3A-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Translation termination | Modulation of termination

  • UniProt: Q9H1J1
  • In branches: TR
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Translation termination|Modulation of termination
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN bucket. The label is useful for curator triage, but no direct GO mapping is appropriate because propagation would add a process, activity, or localization not shared cleanly by all members.
    • [group] Translation|Cytosolic translation|Translation termination
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006415 translational termination]
      rationale: This PN group denotes cytosolic translation termination and release factors. Translational termination is the shared process target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

Projected GO annotations (1)

  • GO:0006415 translational termination | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Translation termination

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q9H1J1
gene_symbol: UPF3A
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: UPF3A (Regulator of nonsense transcripts 3A; hUpf3p/hUPF3L) is a nonsense-mediated mRNA decay (NMD) factor and the paralog of UPF3B. It is a nuclear/cytoplasmic shuttling protein that associates with the exon-junction complex (EJC) deposited upstream of exon-exon junctions on spliced mRNA and acts as a molecular adaptor bridging the EJC to the core NMD machinery, binding UPF2 (and RBM8A/EJC) and helping assemble the UPF1-UPF2-UPF3 surveillance complex that licenses decay of premature-termination-codon-containing mRNAs. UPF3A is only marginally active in promoting NMD compared with UPF3B; because the two paralogs compete for the same MIF4G-III surface of UPF2, UPF3A can act as an NMD antagonist/repressor by sequestering UPF2, and in many tissues UPF3A is itself cleared but is stabilized by binding UPF2 when functional UPF3B is absent. UPF3A also binds spliced mRNA and weakly stimulates translation in vitro, and has been reported to bind telomeric-repeat (TERRA) RNA/DNA in the context of telomere RNA surveillance. Through these activities UPF3A contributes to the magnitude and substrate selectivity of NMD and to paralog-buffering of the NMD pathway during development.
alternative_products:
- name: Isoform 1 (hUpf3p, hUPF3L)
  id: Q9H1J1-1
- name: Isoform 2 (hUpf3pdelta, hUPF3S)
  id: Q9H1J1-2
  sequence_note: VSP_012962
- name: Isoform 3
  id: Q9H1J1-3
  sequence_note: VSP_012961
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: UPF3A shuttles between nucleus and cytoplasm and is active in the cytoplasm, where the UPF1-UPF2-UPF3 surveillance complex assembles; well supported.
    action: ACCEPT
    reason: Cytoplasmic activity is consistent with the NMD adaptor role and experimental localization, and with the phylogenetic inference.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Recruits UPF2 at the cytoplasmic side
- term:
    id: GO:0042162
    label: telomeric repeat DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred telomeric-repeat binding, corroborated by direct evidence that UPF3A associates with telomeric-repeat (TERRA) nucleic acid in telomere RNA surveillance. A specialized, non-core activity.
    action: KEEP_AS_NON_CORE
    reason: Telomeric-repeat binding is experimentally reported (TERRA context) but peripheral to UPF3A's core NMD adaptor function.
    supported_by:
    - reference_id: PMID:17916692
      supporting_text: telomeres are transcribed into telomeric repeat-containing RNA (TERRA).
- term:
    id: GO:0045727
    label: positive regulation of translation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: UPF3A weakly stimulates translation in vitro; the effect is modest and secondary to its NMD role.
    action: KEEP_AS_NON_CORE
    reason: Translation stimulation is reported but described as weak/in vitro; it is a minor, non-core activity relative to the NMD adaptor function.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: weakly stimulates
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based nucleic acid binding (UPF3A has an RRM-like fold and binds RNA). The specific mRNA binding term is more informative.
    action: KEEP_AS_NON_CORE
    reason: Correct but general; the specific GO:0003729 (mRNA binding) better captures UPF3A's RNA-binding activity.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Binds spliced mRNA
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic nuclear localization, consistent with UPF3A's role in associating with the nuclear EJC and shuttling to the cytoplasm.
    action: ACCEPT
    reason: Nuclear localization is supported experimentally (UPF3A associates with the nuclear EJC); agrees with NAS nucleus annotation.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: associating with the nuclear exon
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic cytoplasmic localization, consistent with UPF3A shuttling and recruiting UPF2 at the cytoplasmic side of the nuclear envelope.
    action: ACCEPT
    reason: Agrees with experimental/NAS cytoplasm localization and the NMD adaptor role.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Recruits UPF2 at the cytoplasmic side
- term:
    id: GO:0035145
    label: exon-exon junction complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: UPF3A associates with the exon-junction complex (EJC), serving as the link between the EJC core and the NMD machinery; a core cellular component.
    action: ACCEPT
    reason: EJC association is directly documented (IDA/TAS) and is central to UPF3A's adaptor function.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: serving as link between the EJC core and NMD
- term:
    id: GO:0045727
    label: positive regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA-based electronic annotation of translation stimulation; UPF3A weakly stimulates translation in vitro.
    action: KEEP_AS_NON_CORE
    reason: Reported as weak/in vitro; a minor, non-core activity relative to the NMD adaptor role.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: weakly stimulates
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11163187
  qualifier: enables
  review:
    summary: IntAct interactions with UPF1 (Q92900) and UPF2 (Q9HAU5), the core NMD partners that UPF3A bridges. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central UPF1/UPF2 interactions, but bare protein binding is uninformative; the adaptor role is captured by NMD/EJC terms.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q92900: UPF1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11546873
  qualifier: enables
  review:
    summary: IntAct interaction with RBM8A/Y14 (Q9Y5S9), an EJC core component. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real EJC interaction but bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q9Y5S9: RBM8A'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11546874
  qualifier: enables
  review:
    summary: IntAct interaction with RBM8A/Y14 (Q9Y5S9), an EJC core component. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real EJC interaction but bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q9Y5S9: RBM8A'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12417715
  qualifier: enables
  review:
    summary: IntAct interaction with UPF1 (Q92900). The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally relevant UPF1 interaction but bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q92900: UPF1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19503078
  qualifier: enables
  review:
    summary: IntAct interactions with UPF3B (Q9BZI7-2) and UPF2 (Q9HAU5). The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the paralog UPF3B and UPF2 interactions central to NMD competition, but bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q9BZI7-2: UPF3B'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20479275
  qualifier: enables
  review:
    summary: IntAct interaction with UPF2 (Q9HAU5). The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central UPF2 interaction but bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q9HAU5: UPF2'
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-transferred (mouse) neuron-projection localization. There is no direct human evidence; UPF3A is a broadly expressed nucleocytoplasmic NMD factor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Localization transferred from the mouse ortholog without direct human support; not a core or well-established compartment for UPF3A.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-goa.tsv
      supporting_text: ensembl:ENSMUSP00000037354
- term:
    id: GO:2000623
    label: negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: UPF3A can act as an NMD repressor/antagonist by sequestering UPF2, dampening NMD; ortholog-transferred annotation corroborated by experimental evidence (PMID:27040500).
    action: ACCEPT
    reason: UPF3A's NMD-antagonist role (UPF2 sequestration) is experimentally established and is a genuine, distinctive function; consistent with the ortholog transfer.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: only marginally active in NMD
- term:
    id: GO:0071025
    label: RNA surveillance
  evidence_type: NAS
  original_reference_id: PMID:31131562
  qualifier: involved_in
  review:
    summary: UPF3A participates in RNA surveillance (NMD), the broad quality-control process that distinguishes aberrant from normal mRNAs.
    action: ACCEPT
    reason: RNA surveillance is the overarching process to which UPF3A's NMD adaptor function contributes; well supported.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Involved in nonsense-mediated decay (NMD) of mRNAs containing
- term:
    id: GO:0170010
    label: nonsense-mediated decay complex
  evidence_type: NAS
  original_reference_id: PMID:35640974
  qualifier: part_of
  review:
    summary: UPF3A is a component of the NMD (UPF1-UPF2-UPF3 surveillance) complex, the core cellular-component context for its adaptor function.
    action: ACCEPT
    reason: UPF3A's membership in the UPF surveillance/NMD complex is directly supported (including structures of UPF3A-UPF2); a core cellular component.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: UPF1-UPF2-UPF3 surveillance
- term:
    id: GO:2000623
    label: negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: NAS
  original_reference_id: PMID:31131562
  qualifier: involved_in
  review:
    summary: UPF3A negatively regulates NMD (antagonist/repressor) by competing for UPF2; a genuine, distinctive function.
    action: ACCEPT
    reason: Well supported by the literature on UPF3A as an NMD antagonist (UPF2 sequestration); consistent with UPF3A being only marginally active in promoting decay.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: only marginally active in NMD
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) nucleoplasmic localization, consistent with UPF3A's nuclear EJC association.
    action: ACCEPT
    reason: Agrees with the nuclear localization expected for an EJC-associated NMD factor.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: associating with the nuclear exon
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:11163187
  qualifier: enables
  review:
    summary: UPF3A binds spliced mRNA upstream of exon-exon junctions; a core molecular function underlying its EJC/NMD adaptor role.
    action: ACCEPT
    reason: Directly demonstrated mRNA binding; an informative, core molecular function.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Binds spliced mRNA
- term:
    id: GO:0140311
    label: protein sequestering activity
  evidence_type: IMP
  original_reference_id: PMID:27040500
  qualifier: enables
  review:
    summary: UPF3A sequesters UPF2, thereby antagonizing/repressing NMD; this protein-sequestering activity is the molecular basis of its NMD-repressor function.
    action: ACCEPT
    reason: Experimentally supported (UPF3A buffers NMD by sequestering UPF2); a genuine, distinctive molecular function for this paralog.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: only marginally active in NMD
- term:
    id: GO:2000623
    label: negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: IPI
  original_reference_id: PMID:27040500
  qualifier: involved_in
  review:
    summary: UPF3A negatively regulates NMD via its interaction with UPF2 (Q9HAU5), sequestering it from the active NMD machinery.
    action: ACCEPT
    reason: Directly supported; the UPF2 interaction underlies UPF3A's NMD-antagonist role.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q9HAU5: UPF2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25220460
  qualifier: enables
  review:
    summary: IntAct interaction with the RNA helicase DHX34 (Q14147), which promotes the surveillance-to-decay transition in NMD. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a functionally relevant DHX34 interaction but bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Interacts with DHX34
- term:
    id: GO:0035145
    label: exon-exon junction complex
  evidence_type: TAS
  original_reference_id: PMID:11546873
  qualifier: part_of
  review:
    summary: UPF3A is part of the exon-junction complex; a core cellular component for its adaptor function.
    action: ACCEPT
    reason: EJC membership is well supported (TAS and IDA); central to UPF3A's role.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: serving as link between the EJC core and NMD
- term:
    id: GO:0035145
    label: exon-exon junction complex
  evidence_type: IDA
  original_reference_id: PMID:16601204
  qualifier: part_of
  review:
    summary: Direct evidence that UPF3A is part of the exon-junction complex; a core cellular component.
    action: ACCEPT
    reason: Directly demonstrated EJC association; central to UPF3A's adaptor function.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: serving as link between the EJC core and NMD
- term:
    id: GO:0042162
    label: telomeric repeat DNA binding
  evidence_type: IDA
  original_reference_id: PMID:17916692
  qualifier: enables
  review:
    summary: Direct evidence that UPF3A associates with telomeric-repeat (TERRA) nucleic acid in telomere RNA surveillance; a specialized, non-core activity.
    action: KEEP_AS_NON_CORE
    reason: Experimentally reported in the TERRA/telomere context, but peripheral to UPF3A's core NMD adaptor function.
    supported_by:
    - reference_id: PMID:17916692
      supporting_text: telomeres are transcribed into telomeric repeat-containing RNA (TERRA).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927813
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization (NMD pathway), consistent with the cytoplasmic phase of NMD where UPF3A acts.
    action: ACCEPT
    reason: Consistent with UPF3A's cytoplasmic NMD-adaptor activity.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Recruits UPF2 at the cytoplasmic side
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927832
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization (NMD pathway), redundant with the other cytosol annotations.
    action: ACCEPT
    reason: Consistent with UPF3A's cytoplasmic NMD activity.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Recruits UPF2 at the cytoplasmic side
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927836
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization (NMD pathway).
    action: ACCEPT
    reason: Consistent with UPF3A's cytoplasmic NMD activity.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Recruits UPF2 at the cytoplasmic side
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927889
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization (NMD pathway).
    action: ACCEPT
    reason: Consistent with UPF3A's cytoplasmic NMD activity.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Recruits UPF2 at the cytoplasmic side
- term:
    id: GO:0000184
    label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: IDA
  original_reference_id: PMID:16601204
  qualifier: involved_in
  negated: true
  review:
    summary: NOT annotation. In the assay of PMID:16601204, UPF3A did not function in (canonical) NMD, consistent with UPF3A being only marginally active in promoting decay compared with UPF3B. This negation is an important, deliberate curation.
    action: ACCEPT
    reason: The negated annotation correctly records that UPF3A is largely inactive in canonical NMD (in contrast to UPF3B), aligning with the UniProt statement that UPF3A is only marginally active in NMD and with its NMD-antagonist role.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: only marginally active in NMD
- term:
    id: GO:0045727
    label: positive regulation of translation
  evidence_type: IDA
  original_reference_id: PMID:16601204
  qualifier: involved_in
  review:
    summary: UPF3A weakly stimulates translation in vitro; a minor activity reported alongside its (limited) NMD role.
    action: KEEP_AS_NON_CORE
    reason: Reported as weak/in vitro; a minor, non-core activity relative to the NMD adaptor function.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: weakly stimulates
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14636577
  qualifier: enables
  review:
    summary: IntAct interactions with UPF-pathway partners including UPF2 (Q9HAU5) and a SMG/UPF-complex component (Q92540). The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records interactions relevant to UPF surveillance-complex formation, but bare protein binding is uninformative and not core.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'Q9H1J1; Q9HAU5: UPF2'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:11163187
  qualifier: located_in
  review:
    summary: Nuclear localization (author statement), consistent with UPF3A's nuclear EJC association and nucleocytoplasmic shuttling.
    action: ACCEPT
    reason: Consistent with experimental evidence for nuclear localization of UPF3A.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:11163187
  qualifier: located_in
  review:
    summary: Cytoplasmic localization (author statement), consistent with UPF3A shuttling and the cytoplasmic phase of NMD.
    action: ACCEPT
    reason: Consistent with experimental evidence and the NMD adaptor role.
    supported_by:
    - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
      supporting_text: Recruits UPF2 at the cytoplasmic side
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:11163187
  title: Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon.
  findings:
  - statement: UPF3A binds spliced mRNA, associates with the EJC and the UPF1/UPF2 machinery, and links the EJC to NMD.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches the YAML title; the paper establishes UPF3A as an EJC-associated mRNA-binding NMD factor that bridges the EJC to the UPF1/UPF2 machinery. Anchored to UPF3A GOA IDA annotations for this PMID (GO:0003729 mRNA binding; GO:0005515 binding).
- id: PMID:11546873
  title: Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon-exon junction complex.
  findings:
  - statement: hUpf3/UPF3A is a component of the splicing-dependent exon-exon junction complex (EJC).
    reference_section_type: ABSTRACT
- id: PMID:11546874
  title: Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1.
  findings: []
- id: PMID:12417715
  title: Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay.
  findings: []
- id: PMID:14636577
  title: Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7.
  findings: []
- id: PMID:16601204
  title: Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation.
  findings:
  - statement: UPF3A is part of the EJC and, in contrast to UPF3B, is largely inactive in canonical NMD; it weakly stimulates translation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches the YAML title; directly characterizes UPF3A as an EJC component largely inactive in canonical NMD (vs UPF3B). Anchored to UPF3A GOA IDA annotations for this PMID (GO:0035145 exon-exon junction complex; GO:0000184 NMD).
- id: PMID:17916692
  title: Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends.
  findings:
  - statement: NMD/RNA-surveillance factors including UPF3A associate with telomeric-repeat-containing RNA (TERRA) at chromosome ends.
    reference_section_type: ABSTRACT
- id: PMID:19503078
  title: A UPF3-mediated regulatory switch that maintains RNA surveillance.
  findings: []
- id: PMID:20479275
  title: Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex.
  findings: []
- id: PMID:25220460
  title: The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex.
  findings:
  - statement: UPF3A interacts (RNA-independently) with the RNA helicase DHX34, which promotes the surveillance-to-decay-complex transition in NMD.
    reference_section_type: ABSTRACT
- id: PMID:27040500
  title: The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay.
  findings:
  - statement: UPF3A acts as an NMD antagonist/repressor that sequesters UPF2, buffering NMD; UPF3A and UPF3B have antagonistic roles in governing NMD during development.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Publication not cached, but verified against the GOA evidence for this PMID on UPF3A — an IMP annotation to GO:0140311 (protein sequestering activity) plus IPI to GO:2000623 — which directly supports the UPF3A-as-NMD-antagonist/UPF2-sequestering core function. Title and GOA-backed function are consistent.
- id: PMID:31131562
  title: 'Nonsense-mediated mRNA decay: The challenge of telling right from wrong in a complex transcriptome.'
  findings:
  - statement: UPF3A participates in NMD/RNA surveillance and can both contribute to and repress NMD depending on context.
    reference_section_type: ABSTRACT
- id: PMID:35640974
  title: Structures of nonsense-mediated mRNA decay factors UPF3B and UPF3A in complex with UPF2 reveal molecular basis for competitive binding and for neurodevelopmental disorder-causing mutation.
  findings:
  - statement: Crystal structures show UPF3A and UPF3B bind the same MIF4G-III domain of UPF2 competitively; UPF3A can protect itself from degradation by binding UPF2 when UPF3B is absent.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches the YAML title; provides the structural basis for competitive UPF3A/UPF3B binding to UPF2 (MIF4G-III), supporting the UPF2-competition/self-stabilization aspect of UPF3A function. Anchored to UPF3A GOA annotation for this PMID (GO:0170010 NMD complex).
- id: Reactome:R-HSA-927813
  title: Reactome NMD pathway (cytosol localization of UPF3A)
  findings: []
- id: Reactome:R-HSA-927832
  title: Reactome NMD pathway (cytosol localization of UPF3A)
  findings: []
- id: Reactome:R-HSA-927836
  title: Reactome NMD pathway (cytosol localization of UPF3A)
  findings: []
- id: Reactome:R-HSA-927889
  title: Reactome NMD pathway (cytosol localization of UPF3A)
  findings: []
core_functions:
- description: Nonsense-mediated mRNA decay (NMD) adaptor that associates with the exon-junction complex on spliced mRNA and bridges it to the core NMD machinery, binding UPF2 (and RBM8A/EJC) and helping assemble the UPF1-UPF2-UPF3 surveillance complex that targets premature-termination-codon-containing mRNAs.
  molecular_function:
    id: GO:0003729
    label: mRNA binding
  in_complex:
    id: GO:0170010
    label: nonsense-mediated decay complex
  supported_by:
  - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
    supporting_text: serving as link between the EJC core and NMD
  - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
    supporting_text: Binds spliced mRNA
- description: NMD modulator/antagonist; UPF3A is only marginally active in promoting decay and competes with UPF3B for UPF2, sequestering UPF2 to repress/buffer NMD, contributing to paralog-dependent control of NMD magnitude.
  molecular_function:
    id: GO:0140311
    label: protein sequestering activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/UPF3A/UPF3A-uniprot.txt
    supporting_text: only marginally active in NMD
  - reference_id: PMID:35640974
    supporting_text: protect itself from degradation by interaction with UPF2
proposed_new_terms: []
suggested_questions:
- question: Under what physiological/developmental conditions does UPF3A act as an NMD activator (bridging UPF2/EJC) versus an NMD repressor (sequestering UPF2), and what controls the switch?
- question: How does UPF3A protein stability (its clearance in many tissues and stabilization by UPF2 when UPF3B is absent) tune the magnitude of NMD in different cell types?
- question: Are UPF3A's reported telomeric-repeat/TERRA-binding and weak translation-stimulation activities physiologically significant, or incidental to its RRM-based RNA binding?
suggested_experiments:
- description: Degron-controlled UPF3A depletion/restoration (with and without UPF3B) combined with transcriptome-wide NMD-substrate profiling to quantify UPF3A's activator versus repressor contributions across substrate classes.
- description: Structure-guided UPF2-binding mutants of UPF3A that disrupt the competitive MIF4G-III interaction, tested for NMD repression, UPF3A stability, and UPF3B buffering.
- description: Comparative CLIP-seq of UPF3A and UPF3B to define their mRNA/EJC binding landscapes and whether UPF3A binding marks transcripts protected from decay.