id: O94874
gene_symbol: UFL1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: UFL1 (E3 UFM1-protein ligase 1; also called Maxer, NLBP, RCAD, KIAA0776) is the E3 ligase of the UFM1 (ufmylation) cascade, which catalyzes covalent attachment of the ubiquitin-like modifier UFM1 to substrate lysines. UFL1 is the catalytic component of the UFM1 ribosome E3 ligase (UREL) complex together with its obligate cofactor DDRGK1/UFBP1 and CDK5RAP3; DDRGK1 tethers the complex to the endoplasmic-reticulum membrane. Acting as a non-canonical scaffold-type E3, UFL1 activates the E2 enzyme UFC1 to transfer UFM1 onto substrates. Its principal physiological substrate is the 60S ribosomal protein RPL26/uL24, where mono-ufmylation of RPL26 on ER-bound ribosomes weakens the junction between post-termination or stalled 60S subunits and SEC61 translocons, promoting release and recycling of the large subunit and supporting ribosome-associated protein quality control. UFL1 also drives reticulophagy (ER-phagy) and the response to ER stress through ufmylation of ER proteins such as CYB5R3 and RPN1, participates in the DNA-damage response (ufmylating histone H4 and MRE11 to promote ATM activation), and ufmylates additional substrates including TP53/p53, PD-L1 and PD-1, contributing to protein stabilization and immune regulation. UFL1 acts mainly at the ER membrane but is also recruited to sites of DNA damage in the nucleus.
existing_annotations:
- term:
    id: GO:0071568
    label: UFM1 transferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: UFM1 transferase activity is a near-synonymous description of UFL1's E3 UFM1-ligase activity (transfer of UFM1 to substrate).
    action: ACCEPT
    reason: UFL1 is the E3 that mediates UFM1 transfer to substrates; this MF term captures that activity, with GO:0061666 (UFM1 ligase activity) being the most precise E3-step term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: UFL1-mediated ufmylation drives reticulophagy (ER-phagy).
    action: KEEP_AS_NON_CORE
    reason: A genuine downstream process of ER ufmylation; non-core relative to the E3 ligase activity.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: UFL1 acts at the ER membrane as part of the DDRGK1-tethered UREL complex.
    action: ACCEPT
    reason: ER membrane is the principal site of UFL1 catalytic action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: UFL1-mediated ufmylation functions in the ER stress response.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core relative to the E3 ligase activity.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Ufmylation in response to endoplasmic reticulum stress
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UFL1 is recruited to the nucleus/sites of DNA damage; nuclear localization is documented experimentally.
    action: ACCEPT
    reason: Consistent with UFL1's DNA-damage role at double-strand breaks.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Nucleus
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UFL1 localizes to chromosomes/sites of double-strand breaks during the DNA-damage response.
    action: KEEP_AS_NON_CORE
    reason: Documented chromatin localization linked to the DNA-damage role; non-core relative to the principal ER-membrane site of action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Chromosome
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane localization, the principal compartment of UFL1.
    action: ACCEPT
    reason: Correct compartment; corroborated by experimental evidence.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytosolic localization, consistent with UFL1's cytoplasm-facing activity.
    action: KEEP_AS_NON_CORE
    reason: Documented cytoplasmic pool; the principal site of action is the ER membrane.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: UFM1 ligase (E3) activity is the core molecular function of UFL1; this electronic annotation is corroborated by extensive direct experimental evidence.
    action: ACCEPT
    reason: UFL1 is the E3 ligase of the ufmylation cascade; this is its core MF.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: UFL1 is the E3 of protein ufmylation.
    action: ACCEPT
    reason: Core process annotation for the E3 ligase.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but the term is uninformative; core MF is UFM1 ligase activity.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but uninformative term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37595036
  qualifier: enables
  review:
    summary: Interactions with UREL-complex partners. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interactions; non-core under generic term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:37595036
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction record but uninformative term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Cytoplasmic localization (electronic).
    action: KEEP_AS_NON_CORE
    reason: Documented cytoplasmic pool; principal site is the ER membrane.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: UFL1 promotes autophagy/reticulophagy via ER ufmylation, inferred electronically.
    action: KEEP_AS_NON_CORE
    reason: Plausible downstream process; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Role in erythroid/hematopoietic differentiation inferred by similarity.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream developmental role, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Required for hematopoietic stem cell function and hematopoiesis
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ER stress response (electronic), corroborated experimentally.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Ufmylation in response to endoplasmic reticulum stress
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Neuron-projection localization inferred electronically from the ortholog.
    action: KEEP_AS_NON_CORE
    reason: Electronically inferred; peripheral to the core ER-membrane site of action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0043005 neuron projection cellular_component
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: UFL1 negatively regulates T-cell activation via ufmylation/stabilization of PD-1, inferred electronically and shown experimentally.
    action: KEEP_AS_NON_CORE
    reason: Documented immune-regulatory role; downstream, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1
- term:
    id: GO:0060218
    label: hematopoietic stem cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Role in hematopoietic stem cell function inferred by similarity.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream developmental role, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Required for hematopoietic stem cell function and hematopoiesis
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:32807901
  qualifier: involved_in
  review:
    summary: UFL1-mediated ufmylation of TP53/p53 stabilizes it by antagonizing its ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: A documented substrate-specific stabilization effect; downstream of the E3 activity, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Mediates ufmylation of TP53/p53, promoting its stability
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (HPA) ER localization.
    action: ACCEPT
    reason: IDA-supported ER localization consistent with site of action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA GO_REF:0000052
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: EXP
  original_reference_id: PMID:30886146
  qualifier: located_in
  review:
    summary: UFL1 localizes to chromatin/double-strand-break sites during the DNA-damage response (histone H4 ufmylation/ATM activation).
    action: KEEP_AS_NON_CORE
    reason: Documented DNA-damage-associated localization; non-core relative to the principal ER-membrane site.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: recruited to double-strand break sites following DNA damage
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:20018847
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization from the paper identifying UFL1 as the UFM1 E3 ligase.
    action: ACCEPT
    reason: Direct evidence for the principal compartment.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:20164180
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization (NLBP/UFL1).
    action: ACCEPT
    reason: Direct evidence for the principal compartment.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:20228063
  qualifier: located_in
  review:
    summary: Experimental ER membrane localization (RCAD/UFL1).
    action: ACCEPT
    reason: Direct evidence for the principal compartment.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:36121123
  qualifier: involved_in
  review:
    summary: UFL1 is the E3 mediating ufmylation in the scaffold-type complex.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:1990234
    label: transferase complex
  evidence_type: IPI
  original_reference_id: PMID:36121123
  qualifier: part_of
  review:
    summary: UFL1 is the catalytic component of the UREL transferase complex.
    action: ACCEPT
    reason: UFL1 is a bona fide subunit of the UFM1 E3 ligase (transferase) complex.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Catalytic component of the UFM1 ribosome E3 ligase (UREL) complex
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:37795761
  qualifier: is_active_in
  review:
    summary: UFL1 acts at the ER (HRD1 ufmylation study).
    action: ACCEPT
    reason: Direct evidence for the site of action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IDA
  original_reference_id: PMID:32807901
  qualifier: involved_in
  review:
    summary: UFL1 participates in the DNA-damage response (p53 stabilization context).
    action: KEEP_AS_NON_CORE
    reason: A genuine but downstream role of UFL1's ufmylation activity; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Also involved in the response to DNA damage
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:32807901
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of p53).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:35753586
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of P4HB).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37795761
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of HRD1/SYVN1).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:32807901
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates p53.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Mediates ufmylation of TP53/p53, promoting its stability
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:35753586
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates P4HB.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:37795761
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates HRD1/SYVN1.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: SYVN1/HRD1
- term:
    id: GO:0002841
    label: negative regulation of T cell mediated immune response to tumor cell
  evidence_type: IDA
  original_reference_id: PMID:38377992
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates/stabilizes PD-1, suppressing anti-tumor T-cell immunity.
    action: KEEP_AS_NON_CORE
    reason: A documented immune-regulatory role downstream of the E3 activity; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:38377992
  qualifier: involved_in
  review:
    summary: UFL1 ufmylation stabilizes PD-1.
    action: KEEP_AS_NON_CORE
    reason: Substrate-specific stabilization downstream of the E3 activity; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: mediating ufmylation and stabilization of PDCD1/PD-1
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: IDA
  original_reference_id: PMID:38377992
  qualifier: involved_in
  review:
    summary: UFL1 negatively regulates T-cell activation via PD-1 ufmylation.
    action: KEEP_AS_NON_CORE
    reason: Documented immune-regulatory role; downstream, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:36893266
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of PD-L1/CD274).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: CD274/PD-L1
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:38377992
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of PD-1/PDCD1).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: PDCD1/PD-1
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: is_active_in
  review:
    summary: UFL1 acts at the ER membrane within UREL (CYB5R3/ER-phagy study).
    action: ACCEPT
    reason: Direct evidence for the site of action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0045732
    label: positive regulation of protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: involved_in
  review:
    summary: UFL1-mediated ufmylation promotes lysosomal degradation of ufmylated ER proteins (reticulophagy).
    action: KEEP_AS_NON_CORE
    reason: Downstream consequence of ER ufmylation; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: thereby promoting lysosomal degradation of ufmylated proteins
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of CYB5R3).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IMP
  original_reference_id: PMID:37036982
  qualifier: enables
  review:
    summary: Functional evidence for UFL1 UFM1 ligase activity in ER ribosome-associated quality control (RPL26 ufmylation).
    action: ACCEPT
    reason: Direct functional support for the core E3 ligase activity.
    supported_by:
    - reference_id: PMID:37036982
      supporting_text: RQC-dependent degradation of ER-APs strictly requires conjugation of the
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37595036
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity in the mechanistic UREL study.
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates CYB5R3.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:37036982
  qualifier: involved_in
  review:
    summary: UFL1 required for RPL26 ufmylation in ER-RQC.
    action: ACCEPT
    reason: Functional evidence for the core process.
    supported_by:
    - reference_id: PMID:37036982
      supporting_text: UFMylation of translocon-bound 60S subunits modulates the RTJ
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:37595036
  qualifier: involved_in
  review:
    summary: UFL1 mediates ufmylation in the mechanistic UREL study.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IMP
  original_reference_id: PMID:37036982
  qualifier: involved_in
  review:
    summary: UFL1, via RPL26 ufmylation, contributes to release/recycling of stalled 60S ribosomes at the ER, supporting ribosome-associated quality control. This is the major biological process of UFL1.
    action: ACCEPT
    reason: A core physiological role of UFL1 ufmylation - ribosome recycling/RQC at the ER-translocon junction.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37595036
  qualifier: involved_in
  review:
    summary: UFL1 contributes to ribosome recycling/RQC via RPL26 ufmylation.
    action: ACCEPT
    reason: Core physiological role of UFL1 ufmylation.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
- term:
    id: GO:0140501
    label: positive regulation of reticulophagy
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: involved_in
  review:
    summary: UFL1-mediated ufmylation positively regulates reticulophagy.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream process; non-core relative to the E3 activity.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: is_active_in
  review:
    summary: UFL1 acts at the ER membrane within the UREL-60S complex.
    action: ACCEPT
    reason: Direct structural evidence for the site of action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: is_active_in
  review:
    summary: UFL1 acts at the ER membrane within the UREL-60S complex.
    action: ACCEPT
    reason: Direct structural evidence for the site of action.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: UFL1-mediated RPL26 ufmylation promotes release/dissociation of 60S from the ER translocon.
    action: KEEP_AS_NON_CORE
    reason: Genuine role in 60S release/recycling; captured as downstream process, non-core relative to the E3 MF.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: promoting release and recycling of the large ribosomal subunit
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: involved_in
  review:
    summary: UFL1-mediated RPL26 ufmylation promotes 60S release from the ER translocon.
    action: KEEP_AS_NON_CORE
    reason: Genuine role in 60S release/recycling; downstream process, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: promoting release and recycling of the large ribosomal subunit
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:30626644
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (RPL26 is the principal target).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: PMID:30626644
      supporting_text: Ribosomal protein RPL26 is the principal target of UFMylation
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:36121123
  qualifier: enables
  review:
    summary: UFL1 acts as a non-canonical scaffold-type E3, activating UFC1 to transfer UFM1.
    action: ACCEPT
    reason: Direct mechanistic support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: enables
  review:
    summary: Structural/functional evidence for UFL1 E3 ligase activity within the UREL-60S complex.
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: enables
  review:
    summary: Structural evidence for UFL1 E3 ligase activity in the UREL-60S complex.
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: PMID:38383789
      supporting_text: the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:30626644
  qualifier: involved_in
  review:
    summary: UFL1 mediates ufmylation; RPL26 is the principal target.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: PMID:30626644
      supporting_text: Ribosomal protein RPL26 is the principal target of UFMylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: UFL1 mediates RPL26 ufmylation in the UREL-60S complex.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: involved_in
  review:
    summary: UFL1 mediates RPL26 ufmylation in the UREL-60S complex.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: UFL1, via RPL26 ufmylation, contributes to release/recycling of stalled 60S ribosomes at the ER.
    action: ACCEPT
    reason: Core physiological role of UFL1 ufmylation (ribosome recycling/RQC).
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: involved_in
  review:
    summary: UFL1, via RPL26 ufmylation, contributes to release/recycling of stalled 60S ribosomes from the ER translocon.
    action: ACCEPT
    reason: Core physiological role of UFL1 ufmylation (ribosome recycling/RQC).
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: promoting release and recycling of the large ribosomal subunit
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IDA
  original_reference_id: PMID:30783677
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates MRE11 to promote ATM activation in the DNA-damage response.
    action: KEEP_AS_NON_CORE
    reason: A genuine but downstream role of UFL1's ufmylation activity; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: mediates monoufmylation of histone H4 and ufmylation of MRE11
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:30783677
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of MRE11).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: ufmylation of MRE11
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:20164180
  qualifier: is_active_in
  review:
    summary: A reported mitochondrial-outer-membrane localization; UFL1's principal and best-supported site of action is the ER membrane, and this localization is not central to its function.
    action: MARK_AS_OVER_ANNOTATED
    reason: An isolated localization claim at odds with the extensive evidence for ER-membrane action; likely peripheral or context-specific.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005741 mitochondrial outer membrane cellular_component ECO:0000314 IDA PMID:20164180
- term:
    id: GO:0000077
    label: DNA damage checkpoint signaling
  evidence_type: IDA
  original_reference_id: PMID:30886146
  qualifier: involved_in
  review:
    summary: UFL1 promotes ATM activation (a DNA-damage checkpoint kinase) via histone H4 ufmylation.
    action: KEEP_AS_NON_CORE
    reason: A documented downstream signaling role of UFL1 ufmylation; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: mediates monoufmylation of histone H4
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30886146
  qualifier: enables
  review:
    summary: Interaction with NBN/UFC1 in the histone H4 ufmylation/ATM study. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions (including cascade partner UFC1); non-core under generic term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:30886146
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32160526
  qualifier: enables
  review:
    summary: Interaction with DDRGK1 in the ER-phagy screen. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interaction; non-core under generic term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32160526
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:30886146
  qualifier: located_in
  review:
    summary: Direct nuclear localization during the DNA-damage response.
    action: ACCEPT
    reason: Direct evidence for nuclear localization linked to UFL1's DNA-damage role.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Nucleus
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:30886146
  qualifier: located_in
  review:
    summary: Direct cytoplasmic localization.
    action: KEEP_AS_NON_CORE
    reason: Documented cytoplasmic pool; principal site is the ER membrane.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: located_in
  review:
    summary: ER membrane localization from the ER-phagy screen.
    action: ACCEPT
    reason: Direct evidence for the principal compartment.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Positive regulation of autophagy/reticulophagy transferred from ortholog.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream process, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:30886146
  qualifier: enables
  review:
    summary: UFL1 binds the protein kinase ATM (and is phosphorylated by it) in the DNA-damage response.
    action: KEEP_AS_NON_CORE
    reason: A real, specific protein-kinase interaction underlying the DNA-damage role; informative but non-core relative to the E3 ligase activity.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Phosphorylated at Ser-462 by ATM
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Erythroid differentiation role transferred from ortholog.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream developmental role, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Required for hematopoietic stem cell function and hematopoiesis
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: UFL1 functions in the ER stress response.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Ufmylation in response to endoplasmic reticulum stress
- term:
    id: GO:0035861
    label: site of double-strand break
  evidence_type: IDA
  original_reference_id: PMID:30886146
  qualifier: located_in
  review:
    summary: UFL1 is recruited to double-strand-break sites during the DNA-damage response.
    action: KEEP_AS_NON_CORE
    reason: Documented DNA-damage-associated localization; non-core relative to the principal ER-membrane site.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: recruited to double-strand break sites following DNA damage
- term:
    id: GO:0043122
    label: regulation of canonical NF-kappaB signal transduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: NF-kappaB regulatory role transferred from ortholog (UFL1/DDRGK1 axis).
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream signaling role, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0043122 regulation of canonical NF-kappaB signal transduction biological_process ECO:0000250 ISS GO_REF:0000024
- term:
    id: GO:0050727
    label: regulation of inflammatory response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Inflammatory-response regulation transferred from ortholog.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: inflammatory response
- term:
    id: GO:0060218
    label: hematopoietic stem cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Hematopoietic stem cell differentiation transferred from ortholog.
    action: KEEP_AS_NON_CORE
    reason: Plausible by orthology; downstream developmental role, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Required for hematopoietic stem cell function and hematopoiesis
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:30886146
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity (histone H4 ufmylation).
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: mediates monoufmylation of histone H4
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: enables
  review:
    summary: Direct evidence of UFL1 UFM1 ligase activity in the ER-phagy context.
    action: ACCEPT
    reason: Direct support for the core E3 ligase molecular function.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: UFL1 drives reticulophagy via ER ufmylation.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream process; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Involved in reticulophagy in response to endoplasmic reticulum stress
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:30886146
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates histone H4.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: mediates monoufmylation of histone H4
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: UFL1 mediates ufmylation in the ER-phagy context.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:1903895
    label: negative regulation of IRE1-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: UFL1/UREL-dependent ufmylation negatively regulates the IRE1 arm of the UPR (via DDRGK1-IRE1-alpha).
    action: KEEP_AS_NON_CORE
    reason: Documented signaling role downstream of ufmylation; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Ufmylation-dependent reticulophagy inhibits the unfolded protein response
- term:
    id: GO:0061666
    label: UFM1 ligase activity
  evidence_type: IDA
  original_reference_id: PMID:20018847
  qualifier: enables
  review:
    summary: The founding paper identifying UFL1 as the E3 ligase of the UFM1 system, with catalytic activity demonstrated.
    action: ACCEPT
    reason: Original direct demonstration of the core E3 UFM1 ligase activity.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:20531390
  qualifier: part_of
  review:
    summary: UFL1 (Maxer) is part of an ER protein complex; more specifically the UREL complex.
    action: KEEP_AS_NON_CORE
    reason: A generic complex-membership term; the specific and informative term is the UREL transferase complex.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0032991 protein-containing complex cellular_component ECO:0000314 IDA PMID:20531390
- term:
    id: GO:0001649
    label: osteoblast differentiation
  evidence_type: HDA
  original_reference_id: PMID:16210410
  qualifier: involved_in
  review:
    summary: From a membrane-proteomics differentiation study; an HDA association not central to UFL1's defined function.
    action: KEEP_AS_NON_CORE
    reason: High-throughput association of uncertain functional relevance; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0001649 osteoblast differentiation biological_process ECO:0007005 HDA PMID:16210410
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:16210410
  qualifier: located_in
  review:
    summary: Membrane association from proteomics; consistent with UFL1's ER-membrane localization but non-specific.
    action: KEEP_AS_NON_CORE
    reason: Generic membrane term; the specific compartment is the ER membrane.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:1990592
    label: protein K69-linked ufmylation
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: UFL1 mediates ufmylation including K69-linked UFM1 chains.
    action: KEEP_AS_NON_CORE
    reason: Specific chain-linkage sub-aspect of ufmylation; narrow process annotation.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:1990592 protein K69-linked ufmylation biological_process ECO:0000314 IDA PMID:25219498
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20228063
  qualifier: enables
  review:
    summary: Interaction with CDK5RAP3/DDRGK1 (RCAD study). Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interactions; non-core under generic term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20228063
- term:
    id: GO:0033146
    label: regulation of intracellular estrogen receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: UFL1 ufmylates TRIP4/ASC1, affecting ERalpha transactivation.
    action: KEEP_AS_NON_CORE
    reason: A specialized signaling role downstream of ufmylation; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: Interaction with DDRGK1/TRIP4 (ASC1/ufmylation study). Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade-relevant interactions; non-core under generic term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25219498
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:20531390
  qualifier: located_in
  review:
    summary: ER localization (Maxer/UFL1).
    action: ACCEPT
    reason: Direct evidence for the principal compartment.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:20531390
  qualifier: located_in
  review:
    summary: ER membrane localization (Maxer/UFL1).
    action: ACCEPT
    reason: Direct evidence for the principal compartment.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:20531390
  qualifier: acts_upstream_of_or_within
  review:
    summary: Effect on cell proliferation in the Maxer study.
    action: KEEP_AS_NON_CORE
    reason: Downstream cellular phenotype; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0008284 positive regulation of cell population proliferation biological_process ECO:0000315 IMP PMID:20531390
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IMP
  original_reference_id: PMID:20531390
  qualifier: acts_upstream_of_or_within
  review:
    summary: UFL1 affects protein localization in the Maxer study.
    action: KEEP_AS_NON_CORE
    reason: Downstream effect; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0032880 regulation of protein localization biological_process ECO:0000315 IMP PMID:20531390
- term:
    id: GO:0032434
    label: regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:20228063
  qualifier: acts_upstream_of_or_within
  review:
    summary: UFL1 regulates proteasomal degradation (protects CDK5RAP3/itself from ubiquitination).
    action: KEEP_AS_NON_CORE
    reason: Downstream effect on protein turnover; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:23152784
  qualifier: acts_upstream_of_or_within
  review:
    summary: UFL1 is up-regulated by ER stress (thapsigargin) and functions in ER homeostasis.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Up-regulated by thapsigargin
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:23152784
  qualifier: acts_upstream_of_or_within
  review:
    summary: UFL1 is part of the UFM1 conjugation system implicated in ER homeostasis.
    action: ACCEPT
    reason: Supports the core process annotation.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20164180
  qualifier: enables
  review:
    summary: Interaction with CDK5RAP3/LZAP and RELA (NLBP study). Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions (including cascade partner CDK5RAP3); non-core under generic term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20164180
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:20164180
  qualifier: involved_in
  review:
    summary: UFL1 (NLBP) interaction with CDK5RAP3 protects against ubiquitination/degradation.
    action: KEEP_AS_NON_CORE
    reason: A documented effect on partner stability; downstream, non-core.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20164180
  qualifier: located_in
  review:
    summary: Cytoplasmic localization (NLBP/UFL1).
    action: KEEP_AS_NON_CORE
    reason: Documented cytoplasmic pool; principal site is the ER membrane.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20018847
  qualifier: enables
  review:
    summary: Interaction with DDRGK1 and UFC1 in the founding UFM1 E3 ligase paper. Bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interactions; non-core under generic term.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20018847
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:20018847
  qualifier: located_in
  review:
    summary: ER localization from the founding UFM1 E3 ligase paper.
    action: ACCEPT
    reason: Direct evidence for the principal compartment.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:20018847
  qualifier: involved_in
  review:
    summary: Founding demonstration that UFL1 is the E3 of ufmylation.
    action: ACCEPT
    reason: Direct evidence for the core process.
    supported_by:
    - reference_id: file:human/UFL1/UFL1-uniprot.txt
      supporting_text: E3 protein ligase that mediates ufmylation
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 by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation through association of InterPro records with GO terms
  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: PMID:16210410
  title: Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation.
  findings: []
- id: PMID:20018847
  title: A novel type of E3 ligase for the Ufm1 conjugation system.
  findings:
  - statement: UFL1 is the E3 ligase of the UFM1 conjugation system and interacts with DDRGK1 and the E2 UFC1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding paper establishing UFL1 as the UFM1 E3 ligase.
- id: PMID:20164180
  title: A novel LZAP-binding protein, NLBP, inhibits cell invasion.
  findings:
  - statement: UFL1/NLBP interacts with CDK5RAP3/LZAP and RELA and protects partners from ubiquitin-mediated degradation.
    reference_section_type: ABSTRACT
- id: PMID:20228063
  title: A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling.
  findings:
  - statement: UFL1/RCAD interacts with CDK5RAP3 and regulates stability of CDK5RAP3 and DDRGK1, modulating NF-kappaB.
    reference_section_type: ABSTRACT
- id: PMID:20531390
  title: Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity.
  findings:
  - statement: UFL1/Maxer is an ER protein whose suppression contributes to non-cell-autonomous toxicity.
    reference_section_type: ABSTRACT
- id: PMID:23152784
  title: Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking.
  findings:
  - statement: The UFM1 conjugation system (including UFL1) is up-regulated upon ER stress.
    reference_section_type: ABSTRACT
- id: PMID:25219498
  title: Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.
  findings:
  - statement: UFL1 ufmylates TRIP4/ASC1, contributing to ERalpha transactivation.
    reference_section_type: ABSTRACT
- id: PMID:30626644
  title: Ribosomal protein RPL26 is the principal target of UFMylation.
  findings:
  - statement: RPL26 is the principal cellular target of UFMylation.
    reference_section_type: TITLE
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the principal ufmylation substrate.
- id: PMID:30783677
  title: MRE11 UFMylation promotes ATM activation.
  findings:
  - statement: UFL1 ufmylates MRE11 to promote ATM activation in the DNA-damage response.
    reference_section_type: ABSTRACT
- id: PMID:30886146
  title: UFL1 promotes histone H4 ufmylation and ATM activation.
  findings:
  - statement: UFL1 is recruited to double-strand breaks via NBN, ufmylates histone H4, and promotes ATM activation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes UFL1's DNA-damage/ATM role and H4 ufmylation.
- id: PMID:32160526
  title: A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-Resident UFMylation.
  findings:
  - statement: UFL1 and ER-resident UFMylation drive ER-phagy and regulate the IRE1 UPR.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32807901
  title: UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.
  findings:
  - statement: UFL1-mediated ufmylation of TP53/p53 stabilizes p53 by antagonizing its ubiquitination.
    reference_section_type: ABSTRACT
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35753586
  title: P4HB UFMylation regulates mitochondrial function and oxidative stress.
  findings:
  - statement: UFL1 ufmylates P4HB, regulating mitochondrial function and oxidative stress.
    reference_section_type: ABSTRACT
- id: PMID:36121123
  title: A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
  findings:
  - statement: UFL1/DDRGK1 forms a non-canonical scaffold-type E3 (UREL) that activates the E2 UFC1 to ufmylate substrate.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the scaffold-type E3 mechanism with UFL1 as catalytic component.
- id: PMID:36543799
  title: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
  findings:
  - statement: UFL1/UREL ufmylates CYB5R3 to drive ER-phagy.
    reference_section_type: ABSTRACT
- id: PMID:36893266
  title: Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target.
  findings:
  - statement: UFL1 ufmylates CD274/PD-L1, affecting tumor immune evasion.
    reference_section_type: ABSTRACT
- id: PMID:37036982
  title: RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
  findings:
  - statement: UFL1-mediated RPL26 ufmylation is required for ribosome-associated quality control at the ER.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Links UFL1/RPL26 ufmylation to ER-RQC.
- id: PMID:37595036
  title: Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control.
  findings:
  - statement: UFL1, within UREL, mediates RPL26 ufmylation supporting ribosome-associated protein quality control.
    reference_section_type: ABSTRACT
- id: PMID:37795761
  title: UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
  findings:
  - statement: UFL1 ufmylates SYVN1/HRD1, regulating ER homeostasis.
    reference_section_type: ABSTRACT
- id: PMID:38377992
  title: UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity.
  findings:
  - statement: UFL1 ufmylates and stabilizes PDCD1/PD-1, negatively regulating anti-tumor T-cell immunity.
    reference_section_type: ABSTRACT
- id: PMID:38383785
  title: UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.
  findings:
  - statement: The UFL1/DDRGK1/CDK5RAP3 (UREL) complex ufmylates RPL26 to promote recycling of 60S ribosomal subunits from the ER.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cryo-EM structure of UREL on 60S; defines ribosome recycling role.
- id: PMID:38383789
  title: The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
  findings:
  - statement: UREL (UFL1/DDRGK1/CDK5RAP3) wraps around the 60S subunit, ufmylates RPL26, and releases/recycles ribosomes from ER translocons.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structure of UREL on 60S; release of ribosomes from translocons.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
core_functions:
- description: E3 UFM1-protein ligase, the catalytic component of the UFM1 ribosome E3 ligase (UREL) complex (with cofactor DDRGK1 and CDK5RAP3), that acts as a non-canonical scaffold-type E3 to activate the E2 UFC1 and catalyze transfer of UFM1 onto substrate lysines.
  molecular_function:
    id: GO:0061666
    label: UFM1 ligase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/UFL1/UFL1-uniprot.txt
    supporting_text: E3 protein ligase that mediates ufmylation
  - reference_id: PMID:30626644
    supporting_text: Ribosomal protein RPL26 is the principal target of UFMylation
- description: Mediates mono-ufmylation of the 60S ribosomal protein RPL26/uL24 on ER-bound ribosomes, weakening the 60S-SEC61 junction to promote release and recycling of post-termination/stalled large ribosomal subunits, thereby supporting ribosome-associated protein quality control at the ER.
  molecular_function:
    id: GO:0061666
    label: UFM1 ligase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/UFL1/UFL1-uniprot.txt
    supporting_text: plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
  - reference_id: PMID:37036982
    supporting_text: UFMylation of translocon-bound 60S subunits modulates the RTJ
proposed_new_terms: []
suggested_questions:
- question: How is UFL1 substrate selectivity determined across its diverse substrates (RPL26, histone H4, MRE11, p53, PD-1/PD-L1, CYB5R3) - is it driven by DDRGK1/CDK5RAP3 adaptors, localization, or post-translational regulation?
- question: Is the reported mitochondrial-outer-membrane localization of UFL1 a genuine functional pool or carryover from ER-mitochondria contact sites?
- question: How does ATM-mediated phosphorylation of UFL1 at Ser-462 mechanistically enhance its ligase activity in the DNA-damage response?
suggested_experiments:
- description: Substrate-trapping or proximity-labeling proteomics of catalytically active versus inactive UFL1 across ER-stress, DNA-damage and basal conditions to define context-dependent substrate repertoires.
- description: Reconstitute the UREL-60S complex with purified UFL1/DDRGK1/CDK5RAP3 and UFC1 to measure how each subunit and the ATM-phosphorylation site contribute to RPL26 ufmylation and 60S release from SEC61.
- description: Separation-of-function UFL1 alleles tested in ER-RQC reporter, reticulophagy, and DNA-damage (ATM activation) assays to determine whether a single catalytic activity underlies all phenotypes.