id: P61960
gene_symbol: UFM1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UFM1 (ubiquitin-fold modifier 1) is a small (85 aa precursor; 83 aa mature)
  metazoan- and plant-specific ubiquitin-like protein modifier. It is itself the
  covalent tag of the ufmylation pathway, not an enzyme. The precursor is
  processed at its C-terminus (removal of the Ser-Cys dipeptide) to expose
  Gly-83, which is then conjugated via an isopeptide bond to lysine residues of
  substrate proteins as a monomer or a lysine-linked polymer. Conjugation
  (ufmylation) proceeds through a dedicated enzymatic cascade analogous to
  ubiquitylation, comprising the E1-activating enzyme UBA5, the E2-conjugating
  enzyme UFC1, and the E3 ligase UFL1 (with its ER-membrane cofactor
  DDRGK1/UFBP1); it is reversed by the UFM1-specific proteases UFSP1 and UFSP2.
  The principal substrate is the 60S ribosomal protein RPL26 (uL24) on
  endoplasmic-reticulum-bound ribosomes, and ufmylation acts in co-translational
  protein biogenesis at the ER, recycling of 60S ribosomal subunits from the ER,
  reticulophagy (ER-phagy), the response to ER stress, and the DNA-damage
  response. UFM1 is found in the cytoplasm and nucleus, with its conjugation
  machinery enriched at the cytoplasmic surface of the ER. Loss of ufmylation
  causes hypomyelinating leukodystrophy (HLD14) and is essential for embryonic
  and brain development.
alternative_products:
- name: '1'
  id: P61960-1
- name: '2'
  id: P61960-2
  sequence_note: VSP_041186
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      UFM1 is present in the cytoplasm, where much of its conjugation cascade
      operates (the ufmylation machinery is enriched at the cytoplasmic surface
      of the ER). Cytoplasmic localization is directly supported and
      phylogenetically conserved.
    action: ACCEPT
    reason: >-
      Cytoplasm is a well-supported site for UFM1 (direct IDA evidence and
      conserved across the family); consistent with where ufmylation acts.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Ufmylation participates in the cellular response to ER stress; UFM1
      conjugation genes are induced by ER-stress agents and ER-resident
      ufmylation is required for ER homeostasis. This is a genuine downstream
      process of ufmylation rather than UFM1's core molecular role.
    action: KEEP_AS_NON_CORE
    reason: >-
      A bona fide biological process outcome of ufmylation, but downstream of
      and non-core relative to UFM1's molecular role as the protein tag.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      ER-resident ufmylation is required for reticulophagy (ER-phagy); UFM1
      contributes to this selective-autophagy process via its conjugation to
      ER-associated substrates.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine process supported experimentally (genome-wide ER-phagy screen),
      but a downstream consequence of ufmylation rather than UFM1's core
      molecular function.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      UFM1 is detected in the nucleus as well as the cytoplasm. Nuclear
      localization is directly observed and phylogenetically conserved,
      consistent with roles such as the DNA-damage response.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization is supported (IDA), but UFM1's principal site of
      action is cytoplasmic/ER-associated; retained as non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation of nuclear localization, redundant with and
      consistent with the experimentally supported nucleus annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct localization but automated and non-core relative to UFM1's
      cytoplasmic/ER site of action.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation of cytoplasmic localization, consistent with
      stronger experimental and IBA cytoplasm evidence.
    action: ACCEPT
    reason: >-
      Correct compartment for UFM1; agrees with direct experimental evidence.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Protein ufmylation is the core biological process in which UFM1 is the
      conjugated modifier. Strongly supported by direct experimental evidence
      across many studies.
    action: ACCEPT
    reason: >-
      This is UFM1's central biological process; well supported (here by
      sequence/family inference, corroborated by IDA/IMP evidence).
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Ubiquitin-like modifier which can be covalently attached via
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  qualifier: enables
  review:
    summary: >-
      High-throughput autophagy interaction network (Behrends et al.) capturing
      a UFM1 interaction (WITH UBA5, Q9GZZ9). The bare protein binding term is
      uninformative; the recurrent meaningful partner is the E1 enzyme UBA5.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records a real interaction with the E1 (UBA5) but the generic protein
      binding term is uninformative and not core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: >-
      Quantitative human interactome (Hein et al.) capturing a UFM1-UBA5
      (Q9GZZ9) interaction. Generic protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with the E1 (UBA5), but generic and non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26872069
  qualifier: enables
  review:
    summary: >-
      Targeted study reporting interaction of UFM1 with UBA5 (Q9GZZ9) in the
      context of UBA5-mutation ataxia. Generic protein binding term; the
      meaningful partner is the E1 enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, mechanistically relevant interaction with UBA5, but the generic MF
      term is uninformative; the activating interaction itself is captured by
      ufmylation/core MF.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      BioPlex affinity-purification interactome capturing a UFM1 interaction (WITH S100A6, P06703). Isolated high-throughput interaction with a non-cascade partner.
    action: KEEP_AS_NON_CORE
    reason: >-
      Bare protein binding from a single high-throughput screen with a partner (S100A6) unrelated to UFM1's conjugation function; uninformative and not core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-goa.tsv
      supporting_text: UniProtKB:P06703
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Reference binary interactome (HuRI, Luck et al.) capturing UFM1 interactions (WITH INCA1, Q0VD86; KCTD21, Q4G0X4). Isolated Y2H interactions with non-cascade partners.
    action: KEEP_AS_NON_CORE
    reason: >-
      Bare protein binding from a high-throughput Y2H map with partners unrelated to UFM1's conjugation cascade; uninformative and not core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-goa.tsv
      supporting_text: UniProtKB:Q0VD86
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      BioPlex (Huttlin et al.) interactome capturing UFM1 interactions (WITH
      S100A6, P06703; UBA5, Q9GZZ9). The UBA5 interaction is mechanistically
      meaningful; the term itself is generic.
    action: KEEP_AS_NON_CORE
    reason: >-
      Includes the relevant E1 (UBA5) interaction but the generic protein
      binding term is uninformative and non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: >-
      OpenCell endogenous-tagging interactome capturing a UFM1-UBA5 (Q9GZZ9)
      interaction. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with the E1 (UBA5), but generic and non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Multimodal cell-maps interactome capturing a UFM1-UBA5 (Q9GZZ9)
      interaction. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with the E1 (UBA5), but generic and non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      UFM1's conjugation machinery and its principal substrate (RPL26) are at
      the ER-bound ribosome; UFM1 is recruited to and acts at the cytoplasmic
      surface of the ER.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects UFM1's functionally important ER-associated site of action;
      supported by orthology and by the established ER-bound RPL26 ufmylation,
      though by automated transfer here.
    supported_by:
    - reference_id: PMID:30626644
      supporting_text: tethered to the cytoplasmic surface of the ER
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic (orthology) annotation of the ER-stress-response role,
      redundant with the IBA/IDA annotations for the same process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine downstream process of ufmylation; non-core relative to UFM1's
      molecular role.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Orthology-transferred annotation (from rat) for an anti-apoptotic role.
      This is an indirect, organism/context-dependent downstream effect with
      weak support for human UFM1 specifically.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect, context-dependent downstream phenotype supported only by
      orthology transfer; not a direct or core function of UFM1.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-goa.tsv
      supporting_text: negative regulation of apoptotic process
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:30626644
  qualifier: involved_in
  review:
    summary: >-
      Functional genetics establishing UFM1 conjugation to its principal target
      RPL26 on ER-bound ribosomes. Direct support for the core ufmylation
      process.
    action: ACCEPT
    reason: >-
      Core biological process; strongly supported by this RPL26-UFMylation
      study.
    supported_by:
    - reference_id: PMID:30626644
      supporting_text: RPL26 is the principal target of UFM1 conjugation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21304510
  qualifier: enables
  review:
    summary: >-
      Interaction annotation (WITH a mouse partner, Q8VE47). Generic protein
      binding term from an interaction screen; not informative about UFM1's
      molecular role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records an interaction but the generic MF term is uninformative and
      non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-goa.tsv
      supporting_text: UniProtKB:Q8VE47
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27653677
  qualifier: enables
  review:
    summary: >-
      Structural study of the UBA5-UFM1 complex (WITH UBA5, Q9GZZ9) revealing
      the trans-binding mechanism of UFM1 activation. The interaction is
      mechanistically central, though the generic MF term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mechanistically important UBA5 interaction underlying activation, but the
      bare protein binding term is uninformative; the activation step is
      captured by the core ufmylation/tag function.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29295865
  qualifier: enables
  review:
    summary: >-
      Study of trans-binding of UFM1 to UBA5 (Q9GZZ9) that stimulates UBA5
      homodimerization and ATP binding. Mechanistically meaningful E1
      interaction; generic MF term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, mechanistically relevant UBA5 interaction, but the generic protein
      binding term is uninformative and non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30412706
  qualifier: enables
  review:
    summary: >-
      Structural study of UBA5 N-terminal extension boosting UFM1 activation
      (WITH UBA5, Q9GZZ9). Mechanistically meaningful E1 interaction; generic MF
      term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real UBA5 interaction underlying activation, but the generic MF term is
      uninformative and non-core.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UBA5
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: >-
      Genome-wide ER-phagy screen demonstrating that ER-resident ufmylation is
      required for ER homeostasis/response to ER stress. Genuine downstream
      process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Bona fide ufmylation-dependent process, but downstream of and non-core
      relative to UFM1's molecular tag role.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: >-
      The same genome-wide ER-phagy screen establishes ER-resident ufmylation
      as a key requirement for reticulophagy. Genuine downstream process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Bona fide ufmylation-dependent process; non-core relative to the molecular
      tag function.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:27653677
  qualifier: involved_in
  review:
    summary: >-
      Direct biochemical/structural demonstration of UFM1 activation by UBA5
      supporting its conjugation. Core ufmylation process.
    action: ACCEPT
    reason: Core process directly supported.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Ubiquitin-like modifier which can be covalently attached via
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:30412706
  qualifier: involved_in
  review:
    summary: >-
      Direct demonstration that UFM1 activation by UBA5 supports ufmylation.
      Core process annotation.
    action: ACCEPT
    reason: Core process directly supported.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Ubiquitin-like modifier which can be covalently attached via
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: >-
      Functional genetics linking UFM1 to ufmylation in the ER-phagy context.
      Core process annotation.
    action: ACCEPT
    reason: Core process; supported by functional perturbation.
    supported_by:
    - reference_id: PMID:32160526
      supporting_text: ER-Resident UFMylation
- term:
    id: GO:0007420
    label: brain development
  evidence_type: IMP
  original_reference_id: PMID:29868776
  qualifier: involved_in
  review:
    summary: >-
      Biallelic UFM1 (and UFC1) mutations cause hypomyelinating leukodystrophy
      with severe brain involvement, establishing an essential role of
      ufmylation in brain development. This is an organismal/developmental
      phenotype downstream of impaired ufmylation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine, well-supported developmental role, but it is a downstream
      organismal consequence of ufmylation rather than UFM1's core molecular
      function.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: expand the essential role of ufmylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29868776
  qualifier: enables
  review:
    summary: >-
      Interaction of UFM1 with UFC1 (Q9Y3C8, the E2 enzyme) reported in the
      HLD14 study. Mechanistically meaningful cascade interaction; generic MF
      term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real interaction with the E2 (UFC1) underlying conjugation, but the
      generic protein binding term is uninformative; captured by the core
      ufmylation function.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Interacts with UFC1
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:29868776
  qualifier: involved_in
  review:
    summary: >-
      HLD14 disease genetics. The R81C variant decreases UFM1 thioester
      formation with UBA5/UFC1 and decreases ufmylation, directly implicating
      UFM1 in the ufmylation process. Core process annotation.
    action: ACCEPT
    reason: >-
      Core ufmylation process supported by disease-variant functional
      characterization.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: decreased ability to form
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:28393202
  qualifier: part_of
  review:
    summary: >-
      Direct nuclear localization of UFM1. Consistent with the documented
      nucleus/cytoplasm dual localization. The part_of qualifier is unusual for
      a soluble modifier.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization is supported but non-core relative to UFM1's
      principal cytoplasmic/ER site of action.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:28393202
  qualifier: part_of
  review:
    summary: >-
      Direct cytoplasmic localization of UFM1, consistent with its primary site
      of action. The part_of qualifier is unusual for a soluble modifier.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well supported and consistent with where
      ufmylation acts.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0042308
    label: negative regulation of protein import into nucleus
  evidence_type: IMP
  original_reference_id: PMID:28393202
  qualifier: involved_in
  review:
    summary: >-
      A single low-throughput (CACAO) annotation proposing UFM1 negatively
      regulates nuclear protein import. This is a narrow, context-specific claim
      not corroborated by the broader UFM1 literature.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Isolated, context-specific annotation not central to UFM1 biology and not
      corroborated by the principal ufmylation literature.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-goa.tsv
      supporting_text: negative regulation of protein import into nucleus
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence/orthology-based ER localization, consistent with UFM1 acting at
      the ER-bound ribosome where its principal substrate RPL26 is ufmylated.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects UFM1's functionally important ER-associated site of action,
      though by orthology transfer; non-core compartment annotation.
    supported_by:
    - reference_id: PMID:30626644
      supporting_text: tethered to the cytoplasmic surface of the ER
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence/orthology-based anti-apoptotic annotation, redundant with the IEA
      annotation for the same process. Indirect, context-dependent downstream
      effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect downstream phenotype supported only by orthology transfer; not a
      direct or core function of UFM1.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-goa.tsv
      supporting_text: negative regulation of apoptotic process
- term:
    id: GO:1990592
    label: protein K69-linked ufmylation
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: >-
      UFM1 can be conjugated as a Lys-linked polymer; Lys-69 is a UFM1-UFM1
      linkage site (auto-ufmylation/poly-UFM1 chains), directly demonstrated. A
      specific molecular aspect of the core ufmylation process.
    action: ACCEPT
    reason: >-
      Specific, experimentally supported ufmylation chain-linkage process
      directly involving UFM1 (its Lys-69 crosslink), corroborated by the
      UniProt CROSSLNK feature.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Glycyl lysine isopeptide (Lys-Gly) (interchain with
- 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: >-
      Ufmylation of the substrate ASC1 (TRIP4) regulates ERalpha
      transactivation in breast cancer. This is a substrate-specific downstream
      signaling outcome of ufmylation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Substrate-specific (ASC1) downstream signaling consequence of ufmylation;
      non-core relative to UFM1's molecular tag role.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Modification of ASC1 by UFM1 is crucial for ERalpha transactivation
- 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: >-
      The UFM1 conjugation system is transcriptionally up-regulated upon
      ER-stress and vesicle-trafficking disturbance (e.g. thapsigargin), placing
      ufmylation within the ER-stress response. Genuine downstream process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine ufmylation-associated process, but downstream of and non-core
      relative to UFM1's molecular role.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Up-regulated by thapsigargin
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:15071506
  qualifier: located_in
  review:
    summary: >-
      The founding UFM1 study directly observed nuclear localization. Consistent
      with the documented nucleus/cytoplasm dual localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported nuclear localization, but non-core relative to UFM1's principal
      cytoplasmic/ER site of action.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15071506
  qualifier: located_in
  review:
    summary: >-
      The founding UFM1 study directly observed cytoplasmic localization, the
      primary site where the ufmylation cascade operates.
    action: ACCEPT
    reason: >-
      Well-supported cytoplasmic localization consistent with UFM1's site of
      action.
    supported_by:
    - reference_id: file:human/UFM1/UFM1-uniprot.txt
      supporting_text: Cytoplasm
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:15071506
  qualifier: involved_in
  review:
    summary: >-
      The founding study established the UFM1 conjugation system (E1 UBA5, E2
      UFC1) and that UFM1 conjugates to target proteins. Direct support for the
      core ufmylation process.
    action: ACCEPT
    reason: >-
      Core biological process directly demonstrated in the defining UFM1 paper.
    supported_by:
    - reference_id: PMID:15071506
      supporting_text: it conjugates to the
core_functions:
- description: >-
    UFM1 is the covalent protein tag of the ufmylation system. After C-terminal
    processing to expose Gly-83, it is conjugated through an isopeptide bond to
    substrate lysines via the E1 (UBA5), E2 (UFC1) and E3 (UFL1/DDRGK1) cascade;
    it is the modifier, not an enzyme.
  molecular_function:
    id: GO:0031386
    label: protein tag activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: file:human/UFM1/UFM1-uniprot.txt
    supporting_text: Ubiquitin-like modifier which can be covalently attached via
  - reference_id: PMID:15071506
    supporting_text: it conjugates to the
- description: >-
    Through its conjugation, UFM1 participates in protein ufmylation,
    principally targeting the 60S ribosomal protein RPL26 on ER-bound ribosomes
    to support co-translational ER protein biogenesis and 60S subunit recycling
    from the ER.
  molecular_function:
    id: GO:0031386
    label: protein tag activity
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: PMID:30626644
    supporting_text: RPL26 is the principal target of UFM1 conjugation
  directly_involved_in:
  - id: GO:0071569
    label: protein ufmylation
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond RPL26, what is the full repertoire of physiological UFM1 substrates,
    and how is substrate selection determined by the UFL1/DDRGK1 E3 module?
- question: >-
    How do monomeric versus K69-linked poly-UFM1 chains differ in their
    signaling outputs (e.g. ribosome recycling versus reticulophagy versus the
    DNA-damage response)?
- question: >-
    What is the mechanistic basis by which loss of UFM1 conjugation causes
    hypomyelinating leukodystrophy and is essential for brain development?
suggested_experiments:
- description: >-
    Site-specific proteomics (e.g. K-GG-style enrichment adapted for UFM1
    remnants) across tissues and stress conditions to define the comprehensive
    UFMylated proteome beyond RPL26.
- description: >-
    Reconstitution of the full ER-tethered ufmylation/de-ufmylation cycle in
    vitro with defined UBA5/UFC1/UFL1/DDRGK1 and 60S ribosomes to dissect how
    UFM1 conjugation drives 60S recycling.
- description: >-
    Structure-function analysis of poly-UFM1 chain linkages (K69 vs monomer)
    using chain-defective UFM1 mutants to test which downstream processes
    require polymeric versus monomeric ufmylation.
references:
- 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:0000107
  title: >-
    Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15071506
  title: A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier.
  findings:
  - statement: >-
      Defined UFM1 as a ubiquitin-fold modifier conjugated to target proteins
      via a cascade of the E1-like enzyme UBA5 and E2-like enzyme UFC1, after
      C-terminal processing exposes the conserved Gly residue.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding paper defining the UFM1 conjugation system; PubMed-verified.
- id: PMID:20562859
  title: Network organization of the human autophagy system.
  findings: []
- id: PMID:21304510
  title: The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice.
  findings: []
- 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 is transcriptionally up-regulated by ER-stress
      agents (e.g. thapsigargin), linking ufmylation to ER homeostasis.
    reference_section_type: ABSTRACT
- id: PMID:25219498
  title: >-
    Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.
  findings:
  - statement: >-
      Ufmylation of ASC1 (TRIP4) regulates ERalpha transactivation; UFM1 is
      conjugated and can form K69-linked polymers.
    reference_section_type: ABSTRACT
- id: PMID:26496610
  title: >-
    A human interactome in three quantitative dimensions organized by
    stoichiometries and abundances.
  findings: []
- id: PMID:26872069
  title: UBA5 mutations cause a new form of autosomal recessive cerebellar ataxia.
  findings: []
- id: PMID:27653677
  title: >-
    Trans-binding mechanism of ubiquitin-like protein activation revealed by a
    UBA5-UFM1 Complex.
  findings:
  - statement: >-
      Structural basis of UFM1 activation by the E1 UBA5 via a trans-binding
      mechanism.
    reference_section_type: ABSTRACT
- id: PMID:28393202
  title: 'Ufm1 inhibits LPS-induced endothelial cell inflammatory responses through the NF-κB signaling pathway.'
  findings: []
- id: PMID:28514442
  title: >-
    Architecture of the human interactome defines protein communities and
    disease networks.
  findings: []
- id: PMID:29295865
  title: >-
    Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP
    binding.
  findings:
  - statement: >-
      UFM1 trans-binding stimulates UBA5 homodimerization and ATP binding, a
      step in UFM1 activation.
    reference_section_type: ABSTRACT
- id: PMID:29868776
  title: >-
    Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in
    brain development.
  findings:
  - statement: >-
      Biallelic UFM1/UFC1 mutations cause hypomyelinating leukodystrophy; the
      UFM1 R81C variant decreases thioester formation with UBA5/UFC1 and reduces
      ufmylation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Disease genetics establishing the essential developmental role of
      ufmylation.
- id: PMID:30412706
  title: >-
    An N-terminal extension to UBA5 adenylation domain boosts UFM1 activation:
    isoform-specific differences in ubiquitin-like protein activation.
  findings:
  - statement: >-
      A UBA5 N-terminal extension boosts UFM1 activation; structural
      characterization of the UBA5-UFM1 interaction.
    reference_section_type: ABSTRACT
- id: PMID:30626644
  title: Ribosomal protein RPL26 is the principal target of UFMylation.
  findings:
  - statement: >-
      RPL26 is the principal UFM1 conjugation target; UFMylation and
      de-UFMylation occur on the cytoplasmic surface of the ER and UFMylated
      RPL26 is enriched on ER-bound ribosomes and polysomes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies the principal physiological substrate of UFM1; PubMed-verified.
- id: PMID:32160526
  title: >-
    A genome-wide ER-phagy screen highlights key roles of mitochondrial
    metabolism and ER-Resident UFMylation.
  findings:
  - statement: >-
      ER-resident UFMylation is a key requirement for reticulophagy (ER-phagy)
      and ER homeostasis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Links ER-resident ufmylation to ER-phagy.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: >-
    Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []