UFC1

UniProt ID: Q9Y3C8
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
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.
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.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
UFC1 is_active_in GO:0005737 cytoplasm
GO:0071568 UFM1 transferase activity
IBA
GO_REF:0000033 		ACCEPT
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).
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.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
E2-like enzyme which specifically catalyzes the second step in ufmylation
GO:0034976 response to endoplasmic reticulum stress
IBA
GO_REF:0000033 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
Ufmylation is involved in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy
GO:0061709 reticulophagy
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: UFC1, as the cascade E2, contributes to reticulophagy (ER-phagy) driven by ER-resident ufmylation.
Reason: Reticulophagy is a downstream process of ER ufmylation; a valid but non-core process annotation for the E2 enzyme.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
Ufmylation is involved in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy
GO:0061657 UFM1 conjugating enzyme activity
IEA
GO_REF:0000120 		ACCEPT
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.
Reason: UFM1 conjugating enzyme (E2) activity is the core molecular function of UFC1, supported by founding biochemistry and structures.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage
GO:0071569 protein ufmylation
IEA
GO_REF:0000120 		ACCEPT
Summary: Protein ufmylation is the biological process that the UFC1 E2 step belongs to.
Reason: UFC1 is an essential catalytic component of ufmylation; the process annotation is well supported.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
E2-like enzyme which specifically catalyzes the second step in ufmylation
GO:0005515 protein binding
IPI
PMID:25902260
Autism and intellectual disability-associated KIRREL3 intera... 		KEEP AS NON CORE
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.
Reason: Bare protein binding from a single screen with a non-cascade partner does not inform UFC1's core E2 function.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25902260 UniProtKB:Q8IZU9
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: Binary interactome (HuRI) interactions. Bare protein binding is uninformative.
Reason: Records real high-throughput interactions but the term itself is uninformative; the core MF is captured by UFM1 conjugating enzyme activity.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:P57678
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: Neurodegeneration interactome screen interaction. Bare protein binding is uninformative and the partner is not part of the cascade.
Reason: Single high-throughput interaction unrelated to UFC1's catalytic function.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32814053 UniProtKB:O60260-5
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex affinity-purification interaction with UFL1 (O94874), the cognate E3 ligase. This is a genuine cascade interaction, but the bare term is uninformative.
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.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:O94874
GO:0005515 protein binding
IPI
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		KEEP AS NON CORE
Summary: Interaction with UFL1 (O94874) reported in the mechanistic study of the UFM1 E3 ligase complex. Genuine cascade interaction; bare term is uninformative.
Reason: Partner is a core UREL-complex component; real but non-core under the generic term.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:37595036 UniProtKB:O94874
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Multimodal cell-maps interaction with CDK5RAP3 (Q96JB5), a UREL-complex component. Bare protein binding is uninformative.
Reason: Real interaction with a cascade-associated protein; non-core under generic term.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:Q96JB5
GO:0032649 regulation of type II interferon production
IEA
GO_REF:0000107 		KEEP AS NON CORE
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.
Reason: Plausible electronic transfer reflecting ufmylation's role in immune signaling; peripheral to UFC1's catalytic function.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
interferon response
GO:0032649 regulation of type II interferon production
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence-similarity transfer from the mouse ortholog for the same immune-signaling role.
Reason: Same rationale as the IEA annotation; non-core, plausible by orthology.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
interferon response
GO:0061657 UFM1 conjugating enzyme activity
IDA
PMID:34588452
Structural basis for UFM1 transfer from UBA5 to UFC1. 		ACCEPT
Summary: Structural/biochemical demonstration of UFM1 transfer from UBA5 to UFC1, establishing UFC1's E2 conjugating activity directly.
Reason: Direct experimental evidence for the core E2 function; structures show activation of the UFC1 active site upon UBA5 binding.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage
GO:0071569 protein ufmylation
IDA
PMID:34588452
Structural basis for UFM1 transfer from UBA5 to UFC1. 		ACCEPT
Summary: Direct evidence that UFC1 participates in ufmylation via UFM1 transfer.
Reason: Well-supported process annotation for the cascade E2.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
E2-like enzyme which specifically catalyzes the second step in ufmylation
GO:0061657 UFM1 conjugating enzyme activity
IMP
PMID:37036982
RPL26/uL24 UFMylation is essential for ribosome-associated q... 		ACCEPT
Summary: Functional (mutant/knockout) evidence that UFC1 conjugating activity is required for RPL26/uL24 ufmylation and ER ribosome-associated quality control.
Reason: Direct functional support for the core E2 activity in the physiological RQC context.
Supporting Evidence:
PMID:37036982
RQC-dependent degradation of ER-APs strictly requires conjugation of the
GO:0071569 protein ufmylation
IMP
PMID:37036982
RPL26/uL24 UFMylation is essential for ribosome-associated q... 		ACCEPT
Summary: UFC1 is required for ufmylation of 60S ribosomes at the ER, supporting the process annotation.
Reason: Functional evidence ties UFC1 to ER ribosome ufmylation.
Supporting Evidence:
PMID:37036982
UFMylation of translocon-bound 60S subunits modulates the RTJ
GO:0061657 UFM1 conjugating enzyme activity
IDA
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: Demonstration that the UFL1/DDRGK1 scaffold-type E3 activates UFC1 for aminolysis (UFM1 transfer); UFC1 Lys-108 is required.
Reason: Direct biochemical support for the E2 conjugating activity within the non-canonical E2-E3 mechanism.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0061657 UFM1 conjugating enzyme activity molecular_function ECO:0000314 IDA PMID:36121123
GO:0061657 UFM1 conjugating enzyme activity
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: Structures of the UFC1-UFL1-UFM1-DDRGK1 complex and ribosome ufmylation assays establish UFC1's conjugating activity in the context of 60S recycling.
Reason: Direct structural and functional support for the core E2 activity.
Supporting Evidence:
PMID:38383789
the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26
GO:0071569 protein ufmylation
IMP
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylatio... 		ACCEPT
Summary: UFC1 is required for ufmylation; RPL26 identified as the principal target.
Reason: Functional support for UFC1's role in ufmylation.
Supporting Evidence:
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation
GO:0071569 protein ufmylation
IDA
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: Direct evidence that UFC1, activated by the scaffold E3, ufmylates substrate.
Reason: Supports the process annotation for the E2.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0071569 protein ufmylation biological_process ECO:0000314 IDA PMID:36121123
GO:0071569 protein ufmylation
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: Direct evidence for UFC1-dependent ufmylation of 60S ribosomes.
Reason: Supports the process annotation.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0071569 protein ufmylation biological_process ECO:0000314 IDA PMID:38383789
GO:0034976 response to endoplasmic reticulum stress
IMP
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: Genome-wide ER-phagy screen implicating ER-resident ufmylation (including the E2 step) in ER stress responses.
Reason: Valid downstream process; non-core relative to the E2 catalytic activity.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
response to DNA damage, interferon response or reticulophagy
GO:0061709 reticulophagy
IMP
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: ER-phagy screen implicating the ufmylation pathway (UFC1 E2 step) in reticulophagy.
Reason: Valid downstream process; non-core.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
reticulophagy
GO:0071569 protein ufmylation
IMP
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		ACCEPT
Summary: ER-phagy screen confirms UFC1 involvement in ufmylation.
Reason: Supports the process annotation.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
E2-like enzyme which specifically catalyzes the second step in ufmylation
GO:0005515 protein binding
IPI
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		KEEP AS NON CORE
Summary: Interaction with UFL1 (O94874) reported in the histone H4 ufmylation/ATM study. Genuine cascade partner; bare term uninformative.
Reason: Real interaction with the cognate E3; non-core under generic term.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:30886146 UniProtKB:O94874
GO:0061657 UFM1 conjugating enzyme activity
IDA
PMID:15071506
A novel protein-conjugating system for Ufm1, a ubiquitin-fol... 		ACCEPT
Summary: Founding paper identifying UFC1 as the E2 that accepts activated UFM1 from UBA5 via thioester linkage; defines the catalytic Cys.
Reason: Original direct demonstration of the core E2 UFM1-conjugating activity.
Supporting Evidence:
PMID:15071506
Activated Ufm1 is then transferred to its cognate
GO:0005515 protein binding
IPI
PMID:29868776
Biallelic UFM1 and UFC1 mutations expand the essential role ... 		KEEP AS NON CORE
Summary: Interactions reported in the disease study (UFM1 P61960 among partners). Bare term uninformative, but reflects a cascade interaction.
Reason: Real cascade interaction (UFM1) but non-core under generic term.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:29868776 UniProtKB:P61960
GO:0007420 brain development
IMP
PMID:29868776
Biallelic UFM1 and UFC1 mutations expand the essential role ... 		KEEP AS NON CORE
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.
Reason: A genuine, disease-supported physiological role, but a pleiotropic developmental outcome rather than UFC1's core molecular function.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development
GO:0071569 protein ufmylation
IMP
PMID:29868776
Biallelic UFM1 and UFC1 mutations expand the essential role ... 		ACCEPT
Summary: Disease variants decrease ufmylation, functionally implicating UFC1 in the process.
Reason: Supports the process annotation with patient-variant evidence.
Supporting Evidence:
file:human/UFC1/UFC1-uniprot.txt
decreased protein ufmylation
GO:1990592 protein K69-linked ufmylation
IDA
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: UFC1 participates in UFM1 conjugation; UFM1 chains can be linked through Lys-69. This specific linkage-type process is part of ufmylation chemistry.
Reason: A specific sub-aspect of ufmylation (chain linkage type); valid but a narrow process annotation relative to the core E2 activity.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:1990592 protein K69-linked ufmylation biological_process ECO:0000314 IDA PMID:25219498
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		MARK AS OVER ANNOTATED
Summary: Detection of UFC1 in urinary exosome proteomics. This reflects proteomic presence rather than a functional extracellular localization.
Reason: High-throughput proteomic detection in exosomes does not reflect UFC1's cytosolic site of catalytic function.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA PMID:19056867
GO:0034976 response to endoplasmic reticulum stress
IDA
PMID:23152784
Transcriptional regulation of the Ufm1 conjugation system in... 		KEEP AS NON CORE
Summary: The UFM1 conjugation system is transcriptionally up-regulated upon ER stress, consistent with a role in the ER stress response.
Reason: Valid pathway context; non-core relative to catalytic activity.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0034976 response to endoplasmic reticulum stress biological_process ECO:0000314 IDA PMID:23152784
GO:0071569 protein ufmylation
IMP
PMID:23152784
Transcriptional regulation of the Ufm1 conjugation system in... 		ACCEPT
Summary: UFC1 is part of the UFM1 conjugation system implicated in this study.
Reason: Supports the process annotation.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0071569 protein ufmylation biological_process ECO:0000315 IMP PMID:23152784
GO:0005515 protein binding
IPI
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		KEEP AS NON CORE
Summary: Interaction with UFL1 (O94874) from the paper identifying the UFM1 E3 ligase. Genuine cascade interaction; bare term uninformative.
Reason: Real cascade interaction but non-core under generic term; the informative MF is the E2 activity.
Supporting Evidence:
file:human/UFC1/UFC1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20018847 UniProtKB:O94874
GO:0071569 protein ufmylation
IDA
PMID:15071506
A novel protein-conjugating system for Ufm1, a ubiquitin-fol... 		ACCEPT
Summary: Founding biochemical demonstration of the UFM1 conjugation system in which UFC1 is the E2.
Reason: Direct evidence for the process; UFC1 is the cascade E2.
Supporting Evidence:
PMID:15071506
Activated Ufm1 is then transferred to its cognate

Core Functions

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:
UFM1 conjugating enzyme activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/UFC1/UFC1-uniprot.txt
    Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage
  • PMID:15071506
    Activated Ufm1 is then transferred to its cognate

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:15071506
A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier.
  • UFC1 is the E2-like conjugating enzyme that accepts activated UFM1 from the E1 UBA5 via a thioester linkage at its catalytic cysteine.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system.
  • UFL1 is the E3 ligase of ufmylation and interacts with the E2 UFC1 and the cofactor DDRGK1.
PMID:23152784
Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking.
  • The UFM1 conjugation system is transcriptionally up-regulated upon ER stress.
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
PMID:25902260
Autism and intellectual disability-associated KIRREL3 interacts with neuronal proteins MAP1B and MYO16 with potential roles in neurodevelopment.
PMID:29868776
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
  • Biallelic UFC1 variants that impair thioester formation and ufmylation cause a neurodevelopmental disorder, establishing an essential role of ufmylation in brain development.
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation.
  • RPL26 is the principal cellular target of UFMylation.
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation.
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-Resident UFMylation.
  • ER-resident UFMylation is a key regulator of ER-phagy.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34588452
Structural basis for UFM1 transfer from UBA5 to UFC1.
  • UBA5 binding activates the UFC1 active site for UFM1 transfer.
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
  • UFL1/DDRGK1 acts as a scaffold-type E3 that activates the E2 UFC1 for aminolysis; UFC1 Lys-108 is required.
PMID:37036982
RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
  • RQC-dependent degradation of ER arrest products requires UFM1 conjugation to 60S ribosomes at the ribosome-translocon junction.
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control.
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
  • The UFM1 E3 ligase (UREL) wraps around the 60S subunit and ufmylates RPL26 to release/recycle ribosomes from ER translocons.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.

Suggested Questions for Experts

Q: Beyond RPL26/uL24, what is the full physiological substrate repertoire of UFC1-dependent ufmylation, and which substrates are direct E2 products versus E3-determined?

Q: How do the disease variants R23Q and T106I mechanistically reduce thioester formation, and does residual activity correlate with phenotype severity?

Suggested Experiments

Experiment: 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.

Experiment: 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.

πŸ“š Additional Documentation

Notes

(UFC1-notes.md)

UFC1 (Ubiquitin-fold modifier-conjugating enzyme 1) β€” research notes

UniProt: Q9Y3C8 (UFC1_HUMAN), 167 aa. HGNC:26941. Chromosome 1.

Core identity / step in the cascade

UFC1 is the E2 (conjugating) enzyme of the UFM1 (ufmylation) cascade. UFM1 is a
ubiquitin-fold modifier conjugated to substrates via an E1β†’E2β†’E3 cascade analogous to
ubiquitylation. UFC1 accepts activated UFM1 from the E1 enzyme UBA5 and forms a thioester
intermediate at its catalytic Cys-116, then transfers UFM1 to substrate lysines with the
E3 ligase (UFL1/DDRGK1/CDK5RAP3).

  • PMID:15071506 β€” founding paper identifying the UBA5–UFC1 E1/E2 pair.
  • UniProt FUNCTION: "E2-like enzyme which specifically catalyzes the second step in ufmylation ... Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage."
  • Active site Cys-116 (Glycyl thioester intermediate); C116S mutant forms a stable O-ester instead of thioester (UniProt MUTAGEN 116).

Structural / mechanistic

  • PMID:38383789 β€” UREL (UFL1–UFBP1/DDRGK1–CDK5RAP3) wraps around 60S; crystal structure of UFC1 in complex with UFL1/UFM1/DDRGK1 (PDB 8C0D). UFC1 residues Leu-32, Ile-40, Asp-50 mediate UFL1 binding / ribosome ufmylation.
  • PMID:36121123 β€” non-canonical scaffold E3 activates UFC1; Lys-108 of UFC1 required (K108A abolishes ufmylation).
  • UFC1 itself is ufmylated at Lys-122; deufmylated by UFSP1 (PMID:35926457).

Biological roles of the modification (downstream of UFC1 catalysis)

  • RPL26/uL24 on 60S is the principal UFMylation target [PMID:30626644 title "Ribosomal protein RPL26 is the principal target of UFMylation."].
  • ER ribosome-associated quality control: PMID:37036982 β€” UFMylation modulates the ribosome–translocon junction to allow RQC of ER arrest peptides; release/recycling of stalled 60S from ER translocons.
  • Reticulophagy / ER-phagy and response to ER stress: ufmylation pathway implicated (PMID:32160526, ER-phagy screen; PMID:23152784 transcriptional up-regulation of Ufm1 system under ER stress).
  • Regulation of innate immune / interferon signaling: RIG-I signaling regulated by ufmylation (PMID:35394863); regulation of type II interferon production by ISS from mouse ortholog.

Disease

  • Biallelic UFC1 variants cause Neurodevelopmental disorder with spasticity and poor growth (NEDSG, MIM:618076); variants R23Q and T106I decrease thioester formation with UFM1 and decrease ufmylation PMID:29868776. Brain development (IMP) annotation derives from this.

Interactions (IPI annotations in GOA)

Bona fide cascade partners: UBA5 (E1), UFL1 (E3), UFM1 (modifier). GOA IPI partners include
O94874 (UFL1), Q9GZZ9 (UBA5), P61960 (UFM1). Other IPI partners are largely high-throughput
(KIRREL3 Q8IZU9; various). Bare GO:0005515 protein binding is uninformative; the informative
MF is UFM1 conjugating enzyme activity.

Localization

Acts in cytoplasm (IBA) but functions at the ER-bound/translocon-associated ribosome.
Extracellular exosome (HDA) and extracellular region annotations are proteomic-detection
contexts, not the site of function.

Core function conclusion

Core MF: GO:0061657 UFM1 conjugating enzyme activity (E2), acting in GO:0071569 protein
ufmylation in the cytoplasm / at ER-bound ribosomes. GO:0071568 "UFM1 transferase activity"
is a near-synonymous parent reflecting the same activity.

Pn Notes

(UFC1-pn-notes.md)

UFC1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9Y3C8
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 18; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Strong. Notes/review/PN agree UFC1 is the UFM1 E2 (accepts UFM1 from UBA5, Cys-116 thioester, works with UFL1/DDRGK1). Review ACCEPTs GO:0061657 (UFM1 conjugating enzyme activity, IDA x4), GO:0071568 (transferase, IBA), GO:0071569; ERphagy/ER-stress KEEP_AS_NON_CORE. extracellular exosome MARK_AS_OVER_ANNOTATED. No contradictions.
  • PN story / NEW pressure: All PN assertions captured in GOA/review. GO:0006515 (verified) projected new_to_goa via RQC group is broad; UFC1's RQC role is via ufmylation (annotated). Conclusion: already captured; GO:0006515 over-reaches as a direct UFC1 term.
  • Evidence alignment: PN E2 row cites "19452197 / rev" (not in review); review uses cascade/structure PMIDs (15071506, 36121123, 38383789, 37036982 β€” the last three also in GOA as IDA/IMP for GO:0061657). PN ERphagy row cites the ER-phagy screen (PMID:32160526, in notes). Good thematic overlap; PN's family-review PMID is non-overlapping by design.
  • Verdict: Consistent and complete; PN E2/UFMylation/ERphagy story fully captured by specific GO:0061657 + GO:0071569. PN's broad GO:0019787 is an ancestor only; GO:0006515 not warranted as a direct add.

Full Consistency Review

  • UniProt: Q9Y3C8 Β· batch: proteostasis-batch-2026-06-07c Β· review status: complete (core MF GO:0061657; proposed_new_terms: [])
  • PN placement: Translation|Cytosolic translation|Ribosome-associated QC|UFMylation; ALP|...|ERphagy|UFMylation of ER proteins; UPS|E2 conjugating enzymes|UFMylation|no family designation ; PN-node mapping: UFMylation typeβ†’GO:0071569; ERphagyβ†’GO:0061709; E2 groupβ†’GO:0019787 (broad UBL transferase activity, entailed_by_goa_closure); RQC groupβ†’GO:0006515.
  • Consistency: Strong. Notes/review/PN agree UFC1 is the UFM1 E2 (accepts UFM1 from UBA5, Cys-116 thioester, works with UFL1/DDRGK1). Review ACCEPTs GO:0061657 (UFM1 conjugating enzyme activity, IDA x4), GO:0071568 (transferase, IBA), GO:0071569; ERphagy/ER-stress KEEP_AS_NON_CORE. extracellular exosome MARK_AS_OVER_ANNOTATED. No contradictions.
  • PN story / NEW pressure: All PN assertions captured in GOA/review. GO:0006515 (verified) projected new_to_goa via RQC group is broad; UFC1's RQC role is via ufmylation (annotated). Conclusion: already captured; GO:0006515 over-reaches as a direct UFC1 term.
  • Mapping strategy: Specific-vs-broad MF: PN E2-group projects broad GO:0019787 (ubiquitin-like protein transferase activity), explicitly entailed_by_goa_closure of the gene-level specific GO:0061657 β€” so PN's term is strictly an ancestor (TOMM20/HSPA8 "broader" precedent: keep as context, do not propagate over the specific). Review's GO:0061657 (E2) is the correct gene-level MF. UFC1 does not change the node.
  • Evidence alignment: PN E2 row cites "19452197 / rev" (not in review); review uses cascade/structure PMIDs (15071506, 36121123, 38383789, 37036982 β€” the last three also in GOA as IDA/IMP for GO:0061657). PN ERphagy row cites the ER-phagy screen (PMID:32160526, in notes). Good thematic overlap; PN's family-review PMID is non-overlapping by design.
  • Verdict: Consistent and complete; PN E2/UFMylation/ERphagy story fully captured by specific GO:0061657 + GO:0071569. PN's broad GO:0019787 is an ancestor only; GO:0006515 not warranted as a direct add.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/UFC1/UFC1-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | UFMylation

  • UniProt: Q9Y3C8
  • In branches: TR, ALP, UPS
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|UFMylation
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0071569 protein ufmylation]
      rationale: This PN RQC type denotes UFM1 conjugation in ribosome quality control. Protein ufmylation is the shared process target.
    • [group] Translation|Cytosolic translation|Ribosome-associated QC
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
      rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | ERphagy | UFMylation of ER proteins

  • UniProt: Q9Y3C8
  • In branches: TR, ALP, UPS
  • Notes: E2-type protein that catalyzes UFMylation. Knockdown of UFL1 decreased DDRGK1 levels and inhibits ER-phagy.UFL1 UFMylates RPN1 and RPL26 to target ER sheets for degradation.
  • PN references (titles):
    • A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation - ScienceDirect
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|UFMylation of ER proteins
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: This PN subtype captures a specific ER-cargo marking mechanism used in ERphagy. Because GO uses reticulophagy for ER autophagy, this subtype can propagate to reticulophagy.
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: The PN ERphagy marking category captures factors that mark ER cargo for selective autophagic turnover. GO uses reticulophagy for this pathway, so propagation to reticulophagy is appropriate.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | E2 conjugating enzymes | UFMylation | no family designation

  • UniProt: Q9Y3C8
  • In branches: TR, ALP, UPS
  • Signature domains: IPR014806
  • Auxiliary domains: (none)
  • PN references (titles):
    • 19452197 / rev
  • PN-node mapping records (path + ancestors):
    • [type] Ubiquitin Proteasome System|E2 conjugating enzymes|UFMylation|no family designation
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E2 family or architecture subdivision already covered by the curated parent E2 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E2 conjugating enzymes|UFMylation
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0019787 ubiquitin-like protein transferase activity]
      rationale: This PN group is a UBL-conjugating E2 bucket. The safest shared molecular-function target is ubiquitin-like protein transferase activity.
    • [class] Ubiquitin Proteasome System|E2 conjugating enzymes
      status=context_only scope=too_broad_to_propagate GO=[GO:0019787 ubiquitin-like protein transferase activity]
      rationale: This class is a real E2/UBL transferase context, but it includes ubiquitin, SUMO, NEDD8, UFMylation, ATGylation, dual-use, and inactive buckets. Propagation is restricted to narrower curated children.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (5)

  • GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
  • GO:0071569 protein ufmylation | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|UFMylation
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|UFMylation of ER proteins
  • GO:0019787 ubiquitin-like protein transferase activity | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Ubiquitin Proteasome System|E2 conjugating enzymes|UFMylation

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

πŸ“„ View Raw YAML

 
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 ERΞ± 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.