id: Q9Y3C8
gene_symbol: UFC1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: UFC1 (Ubiquitin-fold modifier-conjugating enzyme 1) is the E2-like conjugating enzyme of the UFM1 (ufmylation) cascade, a ubiquitin-like protein-conjugation system that proceeds through E1 (UBA5), E2 (UFC1) and E3 (UFL1/DDRGK1/CDK5RAP3) enzymes. UFC1 accepts the activated ubiquitin-fold modifier UFM1 from the E1 enzyme UBA5 and forms a thioester-linked intermediate at its catalytic cysteine (Cys-116), then, in concert with the UFL1-DDRGK1 E3 ligase, transfers UFM1 onto substrate lysines. The principal physiological substrate is the 60S ribosomal protein RPL26/uL24 on endoplasmic-reticulum-bound ribosomes, where ufmylation promotes recycling of post-termination or stalled 60S subunits from SEC61 translocons and supports ribosome-associated quality control. UFMylation more broadly participates in the response to ER stress, reticulophagy (ER-phagy), DNA-damage signaling and innate-immune/interferon signaling. UFC1 is a small (167 aa) cytosolic protein structurally related to ubiquitin-conjugating (E2) enzymes; biallelic loss-of-function variants cause a neurodevelopmental disorder with spasticity and poor growth, underscoring an essential role of ufmylation in brain development.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: UFC1 is a small soluble protein that acts in the cytoplasm/cytosol, where it receives UFM1 from UBA5 and works with the ER-membrane-anchored UFL1/DDRGK1 E3 to ufmylate ER-bound ribosomes.
    action: ACCEPT
    reason: Cytoplasmic site of action is consistent with the biochemistry of the cascade; UFC1 is a cytosolic E2 that delivers UFM1 to the membrane-tethered E3 complex.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: UFC1 is_active_in GO:0005737 cytoplasm
- 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 parent of the specific E2 UFM1-conjugating activity of UFC1; it captures the same core molecular function (transfer of UFM1).
    action: ACCEPT
    reason: UFC1 catalyzes transfer of UFM1 from a thioester intermediate to substrate; this MF term correctly describes that activity, though GO:0061657 (UFM1 conjugating enzyme activity) is the most precise E2-step term.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: E2-like enzyme which specifically catalyzes the second step in ufmylation
- 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, in which UFC1 is the E2, is induced by and functions in the response to ER stress, linking the modification of ER-bound ribosomes to ER homeostasis.
    action: KEEP_AS_NON_CORE
    reason: This is a downstream biological process that UFC1 participates in via its catalytic role; it is a valid pathway context but non-core relative to the E2 conjugating activity.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: Ufmylation is involved in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: UFC1, as the cascade E2, contributes to reticulophagy (ER-phagy) driven by ER-resident ufmylation.
    action: KEEP_AS_NON_CORE
    reason: Reticulophagy is a downstream process of ER ufmylation; a valid but non-core process annotation for the E2 enzyme.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: Ufmylation is involved in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy
- term:
    id: GO:0061657
    label: UFM1 conjugating enzyme activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: This is the precise E2 molecular function of UFC1 - it forms a thioester intermediate with UFM1 and conjugates it to substrate. Multiple direct experimental annotations corroborate this electronic one.
    action: ACCEPT
    reason: UFM1 conjugating enzyme (E2) activity is the core molecular function of UFC1, supported by founding biochemistry and structures.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage
- 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 biological process that the UFC1 E2 step belongs to.
    action: ACCEPT
    reason: UFC1 is an essential catalytic component of ufmylation; the process annotation is well supported.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: E2-like enzyme which specifically catalyzes the second step in ufmylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25902260
  qualifier: enables
  review:
    summary: IntAct interaction with KIRREL3 (Q8IZU9) from an autism/intellectual-disability interactome screen. Bare protein binding is uninformative and this partner is not part of the ufmylation cascade.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a single screen with a non-cascade partner does not inform UFC1's core E2 function.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25902260 UniProtKB:Q8IZU9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome (HuRI) interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real high-throughput interactions but the term itself is uninformative; the core MF is captured by UFM1 conjugating enzyme activity.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:P57678
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome screen interaction. Bare protein binding is uninformative and the partner is not part of the cascade.
    action: KEEP_AS_NON_CORE
    reason: Single high-throughput interaction unrelated to UFC1's catalytic function.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32814053 UniProtKB:O60260-5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interaction with UFL1 (O94874), the cognate E3 ligase. This is a genuine cascade interaction, but the bare term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The WITH partner is UFL1, a bona fide cascade partner; the interaction is real but the generic term is non-core. The informative MF is the E2 activity.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:O94874
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37595036
  qualifier: enables
  review:
    summary: Interaction with UFL1 (O94874) reported in the mechanistic study of the UFM1 E3 ligase complex. Genuine cascade interaction; bare term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Partner is a core UREL-complex component; real but non-core under the generic term.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:37595036 UniProtKB:O94874
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interaction with CDK5RAP3 (Q96JB5), a UREL-complex component. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with a cascade-associated protein; non-core under generic term.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:Q96JB5
- term:
    id: GO:0032649
    label: regulation of type II interferon production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Inferred from the mouse ortholog; ufmylation regulates innate-immune/interferon signaling, but a specific causal role of UFC1 in type II interferon production in human is not directly demonstrated here.
    action: KEEP_AS_NON_CORE
    reason: Plausible electronic transfer reflecting ufmylation's role in immune signaling; peripheral to UFC1's catalytic function.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: interferon response
- term:
    id: GO:0032649
    label: regulation of type II interferon production
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity transfer from the mouse ortholog for the same immune-signaling role.
    action: KEEP_AS_NON_CORE
    reason: Same rationale as the IEA annotation; non-core, plausible by orthology.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: interferon response
- term:
    id: GO:0061657
    label: UFM1 conjugating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:34588452
  qualifier: enables
  review:
    summary: Structural/biochemical demonstration of UFM1 transfer from UBA5 to UFC1, establishing UFC1's E2 conjugating activity directly.
    action: ACCEPT
    reason: Direct experimental evidence for the core E2 function; structures show activation of the UFC1 active site upon UBA5 binding.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:34588452
  qualifier: involved_in
  review:
    summary: Direct evidence that UFC1 participates in ufmylation via UFM1 transfer.
    action: ACCEPT
    reason: Well-supported process annotation for the cascade E2.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: E2-like enzyme which specifically catalyzes the second step in ufmylation
- term:
    id: GO:0061657
    label: UFM1 conjugating enzyme activity
  evidence_type: IMP
  original_reference_id: PMID:37036982
  qualifier: enables
  review:
    summary: Functional (mutant/knockout) evidence that UFC1 conjugating activity is required for RPL26/uL24 ufmylation and ER ribosome-associated quality control.
    action: ACCEPT
    reason: Direct functional support for the core E2 activity in the physiological RQC context.
    supported_by:
    - reference_id: PMID:37036982
      supporting_text: RQC-dependent degradation of ER-APs strictly requires conjugation of the
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:37036982
  qualifier: involved_in
  review:
    summary: UFC1 is required for ufmylation of 60S ribosomes at the ER, supporting the process annotation.
    action: ACCEPT
    reason: Functional evidence ties UFC1 to ER ribosome ufmylation.
    supported_by:
    - reference_id: PMID:37036982
      supporting_text: UFMylation of translocon-bound 60S subunits modulates the RTJ
- term:
    id: GO:0061657
    label: UFM1 conjugating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:36121123
  qualifier: enables
  review:
    summary: Demonstration that the UFL1/DDRGK1 scaffold-type E3 activates UFC1 for aminolysis (UFM1 transfer); UFC1 Lys-108 is required.
    action: ACCEPT
    reason: Direct biochemical support for the E2 conjugating activity within the non-canonical E2-E3 mechanism.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0061657 UFM1 conjugating enzyme activity molecular_function ECO:0000314 IDA PMID:36121123
- term:
    id: GO:0061657
    label: UFM1 conjugating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: enables
  review:
    summary: Structures of the UFC1-UFL1-UFM1-DDRGK1 complex and ribosome ufmylation assays establish UFC1's conjugating activity in the context of 60S recycling.
    action: ACCEPT
    reason: Direct structural and functional support for the core E2 activity.
    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: IMP
  original_reference_id: PMID:30626644
  qualifier: involved_in
  review:
    summary: UFC1 is required for ufmylation; RPL26 identified as the principal target.
    action: ACCEPT
    reason: Functional support for UFC1's role in ufmylation.
    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:36121123
  qualifier: involved_in
  review:
    summary: Direct evidence that UFC1, activated by the scaffold E3, ufmylates substrate.
    action: ACCEPT
    reason: Supports the process annotation for the E2.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0071569 protein ufmylation biological_process ECO:0000314 IDA PMID:36121123
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:38383789
  qualifier: involved_in
  review:
    summary: Direct evidence for UFC1-dependent ufmylation of 60S ribosomes.
    action: ACCEPT
    reason: Supports the process annotation.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0071569 protein ufmylation biological_process ECO:0000314 IDA PMID:38383789
- 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 implicating ER-resident ufmylation (including the E2 step) in ER stress responses.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream process; non-core relative to the E2 catalytic activity.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: response to DNA damage, interferon response or reticulophagy
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: ER-phagy screen implicating the ufmylation pathway (UFC1 E2 step) in reticulophagy.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream process; non-core.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: reticulophagy
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: involved_in
  review:
    summary: ER-phagy screen confirms UFC1 involvement in ufmylation.
    action: ACCEPT
    reason: Supports the process annotation.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: E2-like enzyme which specifically catalyzes the second step in ufmylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30886146
  qualifier: enables
  review:
    summary: Interaction with UFL1 (O94874) reported in the histone H4 ufmylation/ATM study. Genuine cascade partner; bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with the cognate E3; non-core under generic term.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:30886146 UniProtKB:O94874
- term:
    id: GO:0061657
    label: UFM1 conjugating enzyme activity
  evidence_type: IDA
  original_reference_id: PMID:15071506
  qualifier: enables
  review:
    summary: Founding paper identifying UFC1 as the E2 that accepts activated UFM1 from UBA5 via thioester linkage; defines the catalytic Cys.
    action: ACCEPT
    reason: Original direct demonstration of the core E2 UFM1-conjugating activity.
    supported_by:
    - reference_id: PMID:15071506
      supporting_text: Activated Ufm1 is then transferred to its cognate
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29868776
  qualifier: enables
  review:
    summary: Interactions reported in the disease study (UFM1 P61960 among partners). Bare term uninformative, but reflects a cascade interaction.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interaction (UFM1) but non-core under generic term.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:29868776 UniProtKB:P61960
- term:
    id: GO:0007420
    label: brain development
  evidence_type: IMP
  original_reference_id: PMID:29868776
  qualifier: involved_in
  review:
    summary: Biallelic UFC1 variants (R23Q, T106I) that impair thioester formation and ufmylation cause a neurodevelopmental disorder, establishing an essential role of ufmylation in brain development.
    action: KEEP_AS_NON_CORE
    reason: A genuine, disease-supported physiological role, but a pleiotropic developmental outcome rather than UFC1's core molecular function.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:29868776
  qualifier: involved_in
  review:
    summary: Disease variants decrease ufmylation, functionally implicating UFC1 in the process.
    action: ACCEPT
    reason: Supports the process annotation with patient-variant evidence.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-uniprot.txt
      supporting_text: decreased protein ufmylation
- term:
    id: GO:1990592
    label: protein K69-linked ufmylation
  evidence_type: IDA
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: UFC1 participates in UFM1 conjugation; UFM1 chains can be linked through Lys-69. This specific linkage-type process is part of ufmylation chemistry.
    action: KEEP_AS_NON_CORE
    reason: A specific sub-aspect of ufmylation (chain linkage type); valid but a narrow process annotation relative to the core E2 activity.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:1990592 protein K69-linked ufmylation biological_process ECO:0000314 IDA PMID:25219498
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Detection of UFC1 in urinary exosome proteomics. This reflects proteomic presence rather than a functional extracellular localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput proteomic detection in exosomes does not reflect UFC1's cytosolic site of catalytic function.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19056867
- 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, consistent with a role in the ER stress response.
    action: KEEP_AS_NON_CORE
    reason: Valid pathway context; non-core relative to catalytic activity.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0034976 response to endoplasmic reticulum stress biological_process ECO:0000314 IDA PMID:23152784
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IMP
  original_reference_id: PMID:23152784
  qualifier: acts_upstream_of_or_within
  review:
    summary: UFC1 is part of the UFM1 conjugation system implicated in this study.
    action: ACCEPT
    reason: Supports the process annotation.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0071569 protein ufmylation biological_process ECO:0000315 IMP PMID:23152784
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20018847
  qualifier: enables
  review:
    summary: Interaction with UFL1 (O94874) from the paper identifying the UFM1 E3 ligase. Genuine cascade interaction; bare term uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real cascade interaction but non-core under generic term; the informative MF is the E2 activity.
    supported_by:
    - reference_id: file:human/UFC1/UFC1-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20018847 UniProtKB:O94874
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:15071506
  qualifier: involved_in
  review:
    summary: Founding biochemical demonstration of the UFM1 conjugation system in which UFC1 is the E2.
    action: ACCEPT
    reason: Direct evidence for the process; UFC1 is the cascade E2.
    supported_by:
    - reference_id: PMID:15071506
      supporting_text: Activated Ufm1 is then transferred to its cognate
references:
- 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: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: UFC1 is the E2-like conjugating enzyme that accepts activated UFM1 from the E1 UBA5 via a thioester linkage at its catalytic cysteine.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding paper establishing the UBA5-UFC1 E1/E2 pair; PubMed-verified.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:20018847
  title: A novel type of E3 ligase for the Ufm1 conjugation system.
  findings:
  - statement: UFL1 is the E3 ligase of ufmylation and interacts with the E2 UFC1 and the cofactor DDRGK1.
    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 is transcriptionally 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: []
- id: PMID:25902260
  title: Autism and intellectual disability-associated KIRREL3 interacts with neuronal proteins MAP1B and MYO16 with potential roles in neurodevelopment.
  findings: []
- id: PMID:29868776
  title: Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
  findings:
  - statement: Biallelic UFC1 variants that impair thioester formation and ufmylation cause a neurodevelopmental disorder, establishing an essential role of ufmylation in brain development.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Disease gene paper; UFC1 R23Q/T106I reduce thioester formation.
- 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:30886146
  title: UFL1 promotes histone H4 ufmylation and ATM activation.
  findings: []
- 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 regulator of ER-phagy.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:34588452
  title: Structural basis for UFM1 transfer from UBA5 to UFC1.
  findings:
  - statement: UBA5 binding activates the UFC1 active site for UFM1 transfer.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural mechanism of the E1-to-E2 UFM1 hand-off.
- id: PMID:36121123
  title: A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
  findings:
  - statement: UFL1/DDRGK1 acts as a scaffold-type E3 that activates the E2 UFC1 for aminolysis; UFC1 Lys-108 is required.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the non-canonical E2-E3 mechanism of ufmylation.
- id: PMID:37036982
  title: RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
  findings:
  - statement: RQC-dependent degradation of ER arrest products requires UFM1 conjugation to 60S ribosomes at the ribosome-translocon junction.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Links ribosome 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: []
- id: PMID:38383789
  title: The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
  findings:
  - statement: The UFM1 E3 ligase (UREL) wraps around the 60S subunit and ufmylates RPL26 to release/recycle ribosomes from ER translocons.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structure of UFC1 in the UREL complex bound to 60S.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
core_functions:
- description: E2 UFM1-conjugating enzyme that accepts activated UFM1 from the E1 enzyme UBA5 via a thioester intermediate at its catalytic Cys-116 and, with the UFL1/DDRGK1 E3 ligase, transfers UFM1 onto substrate lysines (notably RPL26/uL24 on ER-bound 60S ribosomes).
  molecular_function:
    id: GO:0061657
    label: UFM1 conjugating enzyme activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/UFC1/UFC1-uniprot.txt
    supporting_text: Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage
  - reference_id: PMID:15071506
    supporting_text: Activated Ufm1 is then transferred to its cognate
proposed_new_terms: []
suggested_questions:
- question: Beyond RPL26/uL24, what is the full physiological substrate repertoire of UFC1-dependent ufmylation, and which substrates are direct E2 products versus E3-determined?
- question: How do the disease variants R23Q and T106I mechanistically reduce thioester formation, and does residual activity correlate with phenotype severity?
suggested_experiments:
- description: Reconstitute the UBA5-UFC1-UFL1/DDRGK1 cascade in vitro with purified components and 60S ribosomes to quantify the kinetic contribution of UFC1 active-site activation to RPL26 ufmylation.
- description: CRISPR knock-in of UFC1 catalytic (C116S) or disease (R23Q/T106I) alleles in cells followed by ribosome-ufmylation and ER-RQC reporter assays to test the requirement of E2 activity for 60S recycling.