id: Q9HAU5
gene_symbol: UPF2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: UPF2 (regulator of nonsense transcripts 2; RENT2) is a core adaptor of the nonsense-mediated mRNA decay (NMD) pathway. Built around tandem MIF4G domains with a C-terminal UPF1-binding region, UPF2 bridges UPF1 (bound to the release factors eRF1/eRF3 at a terminating ribosome) to UPF3B and the exon-junction complex, nucleating the UPF1-UPF2-UPF3 surveillance complex that activates NMD. Binding of UPF2 (together with UPF3B) relieves UPF1 autoinhibition and stimulates its ATPase and RNA helicase activities, committing premature-termination-codon and certain long-3'UTR transcripts to decay. UPF2 acts mainly at the cytoplasmic/perinuclear face of the nuclear envelope and in the cytoplasm, binds spliced mRNA, and has additional reported associations (e.g. telomere/TERRA, mRNA export) peripheral to its core NMD adaptor role.
existing_annotations:
- term:
    id: GO:0035145
    label: exon-exon junction complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: UPF2 is functionally associated with the exon-junction complex; it is recruited by EJC-bound UPF3B and bridges the EJC to UPF1 during NMD.
    action: ACCEPT
    reason: Central to UPF2 function as the EJC-UPF1 bridging adaptor in EJC-dependent NMD.
    supported_by: &id004
    - reference_id: file:human/UPF2/UPF2-uniprot.txt
      supporting_text: Recruited by UPF3B associated with the EJC core
- term:
    id: GO:0000184
    label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Nonsense-mediated mRNA decay is the core biological process of UPF2; it nucleates the UPF1-UPF2-UPF3 surveillance complex that activates NMD.
    action: ACCEPT
    reason: Core NMD process; UPF2 is an essential NMD factor.
    supported_by: &id002
    - reference_id: file:human/UPF2/UPF2-uniprot.txt
      supporting_text: Involved in nonsense-mediated decay (NMD)
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: UPF2 binds spliced mRNA, consistent with its association with mRNP/EJC during NMD.
    action: ACCEPT
    reason: RNA (spliced mRNA) binding is part of UPF2 engagement with target mRNPs.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-uniprot.txt
      supporting_text: Binds spliced mRNA
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, where NMD occurs; UPF2 acts at the cytoplasmic face of the nuclear envelope and in the cytoplasm.
    action: ACCEPT
    reason: Well-supported cytoplasmic/perinuclear localization.
    supported_by: &id001
    - reference_id: file:human/UPF2/UPF2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, perinuclear region'
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Perinuclear region of cytoplasm; UPF2 concentrates at the cytoplasmic side of the nuclear envelope where it meets EJC-bound mRNPs.
    action: ACCEPT
    reason: Directly documented perinuclear localization for UPF2.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, perinuclear region'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11163187
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12417715
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15231747
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15680326
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16086026
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16452507
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16601204
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17469741
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18066079
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18256688
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19150429
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19417104
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19478851
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19503078
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19556969
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20371770
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20479275
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21145460
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22522823
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0071025
    label: RNA surveillance
  evidence_type: NAS
  original_reference_id: PMID:31131562
  qualifier: involved_in
  review:
    summary: RNA surveillance, the broad quality-control category encompassing NMD in which UPF2 is an essential adaptor.
    action: KEEP_AS_NON_CORE
    reason: Accurate high-level descriptor; the specific NMD term is the core annotation.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0071025
- term:
    id: GO:0170010
    label: nonsense-mediated decay complex
  evidence_type: NAS
  original_reference_id: PMID:35640974
  qualifier: part_of
  review:
    summary: UPF2 is a component of the nonsense-mediated decay (UPF1-UPF2-UPF3) surveillance complex.
    action: ACCEPT
    reason: UPF2 is a defining subunit of the NMD effector complex.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0170010
- 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: Negative regulation of NMD; context-dependent modulation of NMD efficiency.
    action: KEEP_AS_NON_CORE
    reason: NAS regulatory annotation; non-core relative to UPF2 driving NMD.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:2000623
- term:
    id: GO:2000624
    label: positive regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: NAS
  original_reference_id: PMID:31131562
  qualifier: involved_in
  review:
    summary: Positive regulation of NMD; UPF2 promotes NMD by stimulating UPF1 ATPase/helicase activity.
    action: KEEP_AS_NON_CORE
    reason: NAS regulatory annotation consistent with UPF2 function; non-core relative to the direct NMD term.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:2000624
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Cytosol localization, consistent with cytoplasmic NMD activity of UPF2.
    action: ACCEPT
    reason: Cytosolic localization agrees with the principal site of UPF2 function.
    supported_by: &id003
    - reference_id: file:human/UPF2/UPF2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, perinuclear region'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, where NMD occurs; UPF2 acts at the cytoplasmic face of the nuclear envelope and in the cytoplasm.
    action: ACCEPT
    reason: Well-supported cytoplasmic/perinuclear localization.
    supported_by: *id001
- term:
    id: GO:0000184
    label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: IMP
  original_reference_id: PMID:19556969
  qualifier: involved_in
  review:
    summary: Nonsense-mediated mRNA decay is the core biological process of UPF2; it nucleates the UPF1-UPF2-UPF3 surveillance complex that activates NMD.
    action: ACCEPT
    reason: Core NMD process; UPF2 is an essential NMD factor.
    supported_by: *id002
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25220460
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23788676
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21829167
  qualifier: located_in
  review:
    summary: Nuclear localization (IDA); a minor UPF2 pool / shuttling consistent with EJC association near the nuclear envelope.
    action: KEEP_AS_NON_CORE
    reason: Minor nuclear pool; the core adaptor function acts at the cytoplasmic/perinuclear face.
    supported_by: &id005
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005634
- term:
    id: GO:0042162
    label: telomeric repeat DNA binding
  evidence_type: IDA
  original_reference_id: PMID:17916692
  qualifier: enables
  review:
    summary: Telomeric repeat DNA binding (IDA); part of a reported NMD-factor association with telomeres/TERRA.
    action: KEEP_AS_NON_CORE
    reason: Telomere-associated activity (PMID:17916692) is a moonlighting role distinct from core NMD adaptor function.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0042162
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20930030
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927813
  qualifier: located_in
  review:
    summary: Cytosol localization, consistent with cytoplasmic NMD activity of UPF2.
    action: ACCEPT
    reason: Cytosolic localization agrees with the principal site of UPF2 function.
    supported_by: *id003
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927832
  qualifier: located_in
  review:
    summary: Cytosol localization, consistent with cytoplasmic NMD activity of UPF2.
    action: ACCEPT
    reason: Cytosolic localization agrees with the principal site of UPF2 function.
    supported_by: *id003
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927836
  qualifier: located_in
  review:
    summary: Cytosol localization, consistent with cytoplasmic NMD activity of UPF2.
    action: ACCEPT
    reason: Cytosolic localization agrees with the principal site of UPF2 function.
    supported_by: *id003
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-927889
  qualifier: located_in
  review:
    summary: Cytosol localization, consistent with cytoplasmic NMD activity of UPF2.
    action: ACCEPT
    reason: Cytosolic localization agrees with the principal site of UPF2 function.
    supported_by: *id003
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17468741
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0035145
    label: exon-exon junction complex
  evidence_type: IDA
  original_reference_id: PMID:16601204
  qualifier: part_of
  review:
    summary: UPF2 is functionally associated with the exon-junction complex; it is recruited by EJC-bound UPF3B and bridges the EJC to UPF1 during NMD.
    action: ACCEPT
    reason: Central to UPF2 function as the EJC-UPF1 bridging adaptor in EJC-dependent NMD.
    supported_by: *id004
- term:
    id: GO:0000184
    label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: IMP
  original_reference_id: PMID:18369367
  qualifier: involved_in
  review:
    summary: Nonsense-mediated mRNA decay is the core biological process of UPF2; it nucleates the UPF1-UPF2-UPF3 surveillance complex that activates NMD.
    action: ACCEPT
    reason: Core NMD process; UPF2 is an essential NMD factor.
    supported_by: *id002
- term:
    id: GO:0000184
    label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: TAS
  original_reference_id: PMID:17468741
  qualifier: involved_in
  review:
    summary: Nonsense-mediated mRNA decay is the core biological process of UPF2; it nucleates the UPF1-UPF2-UPF3 surveillance complex that activates NMD.
    action: ACCEPT
    reason: Core NMD process; UPF2 is an essential NMD factor.
    supported_by: *id002
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11544179
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0000184
    label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
  evidence_type: TAS
  original_reference_id: PMID:16488880
  qualifier: involved_in
  review:
    summary: Nonsense-mediated mRNA decay is the core biological process of UPF2; it nucleates the UPF1-UPF2-UPF3 surveillance complex that activates NMD.
    action: ACCEPT
    reason: Core NMD process; UPF2 is an essential NMD factor.
    supported_by: *id002
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14636577
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16488880
  qualifier: enables
  review:
    summary: Interaction captured under the uninformative generic protein binding term. UPF2 is a central NMD adaptor with many partners (UPF1, UPF3A/B, EJC, SMG factors); this records a real interaction but does not by itself specify function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; retained as non-core because the informative function is its adaptor role bridging UPF1 to UPF3-EJC.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:14636577
  qualifier: located_in
  review:
    summary: Nuclear localization (IDA); a minor UPF2 pool / shuttling consistent with EJC association near the nuclear envelope.
    action: KEEP_AS_NON_CORE
    reason: Minor nuclear pool; the core adaptor function acts at the cytoplasmic/perinuclear face.
    supported_by: *id005
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:14636577
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, where NMD occurs; UPF2 acts at the cytoplasmic face of the nuclear envelope and in the cytoplasm.
    action: ACCEPT
    reason: Well-supported cytoplasmic/perinuclear localization.
    supported_by: *id001
- term:
    id: GO:0006406
    label: mRNA export from nucleus
  evidence_type: TAS
  original_reference_id: PMID:16488880
  qualifier: involved_in
  review:
    summary: mRNA export from nucleus (TAS); a reported ancillary role linked to UPF2/NMD-factor mRNP metabolism.
    action: KEEP_AS_NON_CORE
    reason: Peripheral mRNA-metabolism role; non-core relative to NMD adaptor function.
    supported_by:
    - reference_id: file:human/UPF2/UPF2-goa.tsv
      supporting_text: GO:0006406
core_functions:
- description: NMD adaptor that bridges UPF1 (at the terminating ribosome, with eRF1/eRF3) to UPF3B and the exon-junction complex, nucleating the UPF1-UPF2-UPF3 surveillance complex.
  locations:
  - id: GO:0048471
    label: perinuclear region of cytoplasm
  supported_by:
  - reference_id: file:human/UPF2/UPF2-uniprot.txt
    supporting_text: Recruited by UPF3B associated with the EJC core
  - reference_id: file:human/UPF2/UPF2-uniprot.txt
    supporting_text: Involved in nonsense-mediated decay (NMD)
  in_complex:
    id: GO:0035145
    label: exon-exon junction complex
- description: 'Activator of UPF1 in NMD: UPF2 (with UPF3B) relieves UPF1 autoinhibition and stimulates its ATPase and RNA helicase activities, driving decay of target mRNAs.'
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/UPF2/UPF2-uniprot.txt
    supporting_text: stimulates both ATPase and RNA helicase
  - reference_id: file:human/UPF2/UPF2-goa.tsv
    supporting_text: GO:0000184
  in_complex:
    id: GO:0035145
    label: exon-exon junction complex
proposed_new_terms: []
suggested_questions:
- question: How is the competitive binding of UPF3A versus UPF3B to UPF2 regulated, and how does it tune NMD efficiency on different transcripts?
- question: Which UPF2-dependent NMD branches require the EJC versus operating in EJC-independent NMD?
suggested_experiments:
- description: Domain-resolved UPF2 mutants (MIF4G vs UPF1-binding vs UPF3-binding) with transcriptome-wide NMD-target profiling to separate bridging from UPF1-activation functions.
- description: In vitro reconstitution measuring UPF2/UPF3B stimulation of UPF1 ATPase/helicase activity on EJC-containing substrates to quantify the activation step.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation through association of UniProtKB keywords with GO terms
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:11163187
  title: Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached PMID_11163187 title matches; foundational demonstration that human UPF proteins (including UPF2) target mRNAs for NMD when positioned downstream of a termination codon, supporting the NMD core role."
- id: PMID:11544179
  title: Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay.
  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:15231747
  title: A protein interaction framework for human mRNA degradation.
  findings: []
- id: PMID:15680326
  title: Mammalian Staufen1 recruits Upf1 to specific mRNA 3'UTRs so as to elicit mRNA decay.
  findings: []
- id: PMID:16086026
  title: Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1.
  findings: []
- id: PMID:16452507
  title: Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay.
  findings: []
- id: PMID:16488880
  title: The human RNA surveillance factor UPF1 is required for S phase progression and genome stability.
  findings: []
- id: PMID:16601204
  title: Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation.
  findings: []
- id: PMID:17468741
  title: Human INT6/eIF3e is required for nonsense-mediated mRNA decay.
  findings: []
- id: PMID:17469741
  title: Results of the determination of serum markers in patients with malignant melanoma.
  findings: []
  reference_review:
    relevance: NONE
    correctness: WRONG_IDENTIFIER
    review_notes: Cited as a UPF2 protein binding (IPI) source but the resolved title is a melanoma serum-marker study unrelated to UPF2; appears to be an incorrect identifier in the GOA/IntAct record.
- id: PMID:17916692
  title: Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends.
  findings: []
- id: PMID:18066079
  title: NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached PMID_18066079 title matches; directly establishes both UPF2 core functions - bridging UPF1 to the EJC and stimulating UPF1's RNA helicase activity (supports GO:0000184 NMD role)."
- id: PMID:18256688
  title: Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways.
  findings: []
- id: PMID:18369367
  title: NMD resulting from encephalomyocarditis virus IRES-directed translation initiation seems to be restricted to CBP80/20-bound mRNA.
  findings: []
- id: PMID:19150429
  title: Human proline-rich nuclear receptor coregulatory protein 2 mediates an interaction between mRNA surveillance machinery and decapping complex.
  findings: []
- id: PMID:19417104
  title: SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay.
  findings: []
- id: PMID:19478851
  title: The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay.
  findings: []
- id: PMID:19503078
  title: A UPF3-mediated regulatory switch that maintains RNA surveillance.
  findings: []
- id: PMID:19556969
  title: Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached PMID_19556969 title matches; characterizes the UPF1-UPF2 interaction mode underpinning UPF2's UPF1-activating/bridging function."
- id: PMID:20371770
  title: AAA+ proteins RUVBL1 and RUVBL2 coordinate PIKK activity and function in nonsense-mediated mRNA decay.
  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:20930030
  title: SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay.
  findings: []
- id: PMID:21145460
  title: Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay.
  findings: []
- id: PMID:21829167
  title: Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication.
  findings: []
- id: PMID:22522823
  title: The cryo-EM structure of the UPF-EJC complex shows UPF1 poised toward the RNA 3' end.
  findings: []
- id: PMID:23788676
  title: The RNA helicase Ddx5/p68 binds to hUpf3 and enhances NMD of Ddx17/p72 and Smg5 mRNA.
  findings: []
- id: PMID:25220460
  title: The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
- id: PMID:31131562
  title: 'Nonsense-mediated mRNA decay: The challenge of telling right from wrong in a complex transcriptome.'
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- 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: []
- id: Reactome:R-HSA-927813
  title: 'Reactome: nonsense-mediated decay (cytosol)'
  findings: []
- id: Reactome:R-HSA-927832
  title: 'Reactome: nonsense-mediated decay (cytosol)'
  findings: []
- id: Reactome:R-HSA-927836
  title: 'Reactome: nonsense-mediated decay (cytosol)'
  findings: []
- id: Reactome:R-HSA-927889
  title: 'Reactome: nonsense-mediated decay (cytosol)'
  findings: []