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.
| 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 |
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Download this section (compressed HTML)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?
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.
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