UFM1 (ubiquitin-fold modifier 1) is a small (85 aa precursor; 83 aa mature) metazoan- and plant-specific ubiquitin-like protein modifier. It is itself the covalent tag of the ufmylation pathway, not an enzyme. The precursor is processed at its C-terminus (removal of the Ser-Cys dipeptide) to expose Gly-83, which is then conjugated via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer. Conjugation (ufmylation) proceeds through a dedicated enzymatic cascade analogous to ubiquitylation, comprising the E1-activating enzyme UBA5, the E2-conjugating enzyme UFC1, and the E3 ligase UFL1 (with its ER-membrane cofactor DDRGK1/UFBP1); it is reversed by the UFM1-specific proteases UFSP1 and UFSP2. The principal substrate is the 60S ribosomal protein RPL26 (uL24) on endoplasmic-reticulum-bound ribosomes, and ufmylation acts in co-translational protein biogenesis at the ER, recycling of 60S ribosomal subunits from the ER, reticulophagy (ER-phagy), the response to ER stress, and the DNA-damage response. UFM1 is found in the cytoplasm and nucleus, with its conjugation machinery enriched at the cytoplasmic surface of the ER. Loss of ufmylation causes hypomyelinating leukodystrophy (HLD14) and is essential for embryonic and brain development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: UFM1 is present in the cytoplasm, where much of its conjugation cascade operates (the ufmylation machinery is enriched at the cytoplasmic surface of the ER). Cytoplasmic localization is directly supported and phylogenetically conserved. Reason: Cytoplasm is a well-supported site for UFM1 (direct IDA evidence and conserved across the family); consistent with where ufmylation acts. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Cytoplasm |
| GO:0034976 response to endoplasmic reticulum stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Ufmylation participates in the cellular response to ER stress; UFM1 conjugation genes are induced by ER-stress agents and ER-resident ufmylation is required for ER homeostasis. This is a genuine downstream process of ufmylation rather than UFM1's core molecular role. Reason: A bona fide biological process outcome of ufmylation, but downstream of and non-core relative to UFM1's molecular role as the protein tag. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0061709 reticulophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ER-resident ufmylation is required for reticulophagy (ER-phagy); UFM1 contributes to this selective-autophagy process via its conjugation to ER-associated substrates. Reason: Genuine process supported experimentally (genome-wide ER-phagy screen), but a downstream consequence of ufmylation rather than UFM1's core molecular function. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: UFM1 is detected in the nucleus as well as the cytoplasm. Nuclear localization is directly observed and phylogenetically conserved, consistent with roles such as the DNA-damage response. Reason: Nuclear localization is supported (IDA), but UFM1's principal site of action is cytoplasmic/ER-associated; retained as non-core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation of nuclear localization, redundant with and consistent with the experimentally supported nucleus annotations. Reason: Correct localization but automated and non-core relative to UFM1's cytoplasmic/ER site of action. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of cytoplasmic localization, consistent with stronger experimental and IBA cytoplasm evidence. Reason: Correct compartment for UFM1; agrees with direct experimental evidence. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Cytoplasm |
| GO:0071569 protein ufmylation | IEA GO_REF:0000120 | ACCEPT | Summary: Protein ufmylation is the core biological process in which UFM1 is the conjugated modifier. Strongly supported by direct experimental evidence across many studies. Reason: This is UFM1's central biological process; well supported (here by sequence/family inference, corroborated by IDA/IMP evidence). Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Ubiquitin-like modifier which can be covalently attached via |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | KEEP AS NON CORE | Summary: High-throughput autophagy interaction network (Behrends et al.) capturing a UFM1 interaction (WITH UBA5, Q9GZZ9). The bare protein binding term is uninformative; the recurrent meaningful partner is the E1 enzyme UBA5. Reason: Records a real interaction with the E1 (UBA5) but the generic protein binding term is uninformative and not core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | KEEP AS NON CORE | Summary: Quantitative human interactome (Hein et al.) capturing a UFM1-UBA5 (Q9GZZ9) interaction. Generic protein binding term is uninformative. Reason: Real interaction with the E1 (UBA5), but generic and non-core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| GO:0005515 protein binding | IPI PMID:26872069 UBA5 mutations cause a new form of autosomal recessive cereb... | KEEP AS NON CORE | Summary: Targeted study reporting interaction of UFM1 with UBA5 (Q9GZZ9) in the context of UBA5-mutation ataxia. Generic protein binding term; the meaningful partner is the E1 enzyme. Reason: Real, mechanistically relevant interaction with UBA5, but the generic MF term is uninformative; the activating interaction itself is captured by ufmylation/core MF. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: BioPlex affinity-purification interactome capturing a UFM1 interaction (WITH S100A6, P06703). Isolated high-throughput interaction with a non-cascade partner. Reason: Bare protein binding from a single high-throughput screen with a partner (S100A6) unrelated to UFM1's conjugation function; uninformative and not core. Supporting Evidence: file:human/UFM1/UFM1-goa.tsv UniProtKB:P06703 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Reference binary interactome (HuRI, Luck et al.) capturing UFM1 interactions (WITH INCA1, Q0VD86; KCTD21, Q4G0X4). Isolated Y2H interactions with non-cascade partners. Reason: Bare protein binding from a high-throughput Y2H map with partners unrelated to UFM1's conjugation cascade; uninformative and not core. Supporting Evidence: file:human/UFM1/UFM1-goa.tsv UniProtKB:Q0VD86 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex (Huttlin et al.) interactome capturing UFM1 interactions (WITH S100A6, P06703; UBA5, Q9GZZ9). The UBA5 interaction is mechanistically meaningful; the term itself is generic. Reason: Includes the relevant E1 (UBA5) interaction but the generic protein binding term is uninformative and non-core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: OpenCell endogenous-tagging interactome capturing a UFM1-UBA5 (Q9GZZ9) interaction. Generic protein binding term. Reason: Real interaction with the E1 (UBA5), but generic and non-core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| 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 interactome capturing a UFM1-UBA5 (Q9GZZ9) interaction. Generic protein binding term. Reason: Real interaction with the E1 (UBA5), but generic and non-core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: UFM1's conjugation machinery and its principal substrate (RPL26) are at the ER-bound ribosome; UFM1 is recruited to and acts at the cytoplasmic surface of the ER. Reason: Reflects UFM1's functionally important ER-associated site of action; supported by orthology and by the established ER-bound RPL26 ufmylation, though by automated transfer here. Supporting Evidence: PMID:30626644 tethered to the cytoplasmic surface of the ER |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic (orthology) annotation of the ER-stress-response role, redundant with the IBA/IDA annotations for the same process. Reason: Genuine downstream process of ufmylation; non-core relative to UFM1's molecular role. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Orthology-transferred annotation (from rat) for an anti-apoptotic role. This is an indirect, organism/context-dependent downstream effect with weak support for human UFM1 specifically. Reason: Indirect, context-dependent downstream phenotype supported only by orthology transfer; not a direct or core function of UFM1. Supporting Evidence: file:human/UFM1/UFM1-goa.tsv negative regulation of apoptotic process |
| GO:0071569 protein ufmylation | IMP PMID:30626644 Ribosomal protein RPL26 is the principal target of UFMylatio... | ACCEPT | Summary: Functional genetics establishing UFM1 conjugation to its principal target RPL26 on ER-bound ribosomes. Direct support for the core ufmylation process. Reason: Core biological process; strongly supported by this RPL26-UFMylation study. Supporting Evidence: PMID:30626644 RPL26 is the principal target of UFM1 conjugation |
| GO:0005515 protein binding | IPI PMID:21304510 The Ufm1-activating enzyme Uba5 is indispensable for erythro... | KEEP AS NON CORE | Summary: Interaction annotation (WITH a mouse partner, Q8VE47). Generic protein binding term from an interaction screen; not informative about UFM1's molecular role. Reason: Records an interaction but the generic MF term is uninformative and non-core. Supporting Evidence: file:human/UFM1/UFM1-goa.tsv UniProtKB:Q8VE47 |
| GO:0005515 protein binding | IPI PMID:27653677 Trans-binding mechanism of ubiquitin-like protein activation... | KEEP AS NON CORE | Summary: Structural study of the UBA5-UFM1 complex (WITH UBA5, Q9GZZ9) revealing the trans-binding mechanism of UFM1 activation. The interaction is mechanistically central, though the generic MF term is uninformative. Reason: Mechanistically important UBA5 interaction underlying activation, but the bare protein binding term is uninformative; the activation step is captured by the core ufmylation/tag function. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| GO:0005515 protein binding | IPI PMID:29295865 Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerizati... | KEEP AS NON CORE | Summary: Study of trans-binding of UFM1 to UBA5 (Q9GZZ9) that stimulates UBA5 homodimerization and ATP binding. Mechanistically meaningful E1 interaction; generic MF term. Reason: Real, mechanistically relevant UBA5 interaction, but the generic protein binding term is uninformative and non-core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| GO:0005515 protein binding | IPI PMID:30412706 An N-terminal extension to UBA5 adenylation domain boosts UF... | KEEP AS NON CORE | Summary: Structural study of UBA5 N-terminal extension boosting UFM1 activation (WITH UBA5, Q9GZZ9). Mechanistically meaningful E1 interaction; generic MF term. Reason: Real UBA5 interaction underlying activation, but the generic MF term is uninformative and non-core. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UBA5 |
| 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 demonstrating that ER-resident ufmylation is required for ER homeostasis/response to ER stress. Genuine downstream process. Reason: Bona fide ufmylation-dependent process, but downstream of and non-core relative to UFM1's molecular tag role. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0061709 reticulophagy | IMP PMID:32160526 A genome-wide ER-phagy screen highlights key roles of mitoch... | KEEP AS NON CORE | Summary: The same genome-wide ER-phagy screen establishes ER-resident ufmylation as a key requirement for reticulophagy. Genuine downstream process. Reason: Bona fide ufmylation-dependent process; non-core relative to the molecular tag function. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0071569 protein ufmylation | IDA PMID:27653677 Trans-binding mechanism of ubiquitin-like protein activation... | ACCEPT | Summary: Direct biochemical/structural demonstration of UFM1 activation by UBA5 supporting its conjugation. Core ufmylation process. Reason: Core process directly supported. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Ubiquitin-like modifier which can be covalently attached via |
| GO:0071569 protein ufmylation | IDA PMID:30412706 An N-terminal extension to UBA5 adenylation domain boosts UF... | ACCEPT | Summary: Direct demonstration that UFM1 activation by UBA5 supports ufmylation. Core process annotation. Reason: Core process directly supported. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Ubiquitin-like modifier which can be covalently attached via |
| GO:0071569 protein ufmylation | IMP PMID:32160526 A genome-wide ER-phagy screen highlights key roles of mitoch... | ACCEPT | Summary: Functional genetics linking UFM1 to ufmylation in the ER-phagy context. Core process annotation. Reason: Core process; supported by functional perturbation. Supporting Evidence: PMID:32160526 ER-Resident UFMylation |
| GO:0007420 brain development | IMP PMID:29868776 Biallelic UFM1 and UFC1 mutations expand the essential role ... | KEEP AS NON CORE | Summary: Biallelic UFM1 (and UFC1) mutations cause hypomyelinating leukodystrophy with severe brain involvement, establishing an essential role of ufmylation in brain development. This is an organismal/developmental phenotype downstream of impaired ufmylation. Reason: Genuine, well-supported developmental role, but it is a downstream organismal consequence of ufmylation rather than UFM1's core molecular function. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt expand the essential role of ufmylation |
| GO:0005515 protein binding | IPI PMID:29868776 Biallelic UFM1 and UFC1 mutations expand the essential role ... | KEEP AS NON CORE | Summary: Interaction of UFM1 with UFC1 (Q9Y3C8, the E2 enzyme) reported in the HLD14 study. Mechanistically meaningful cascade interaction; generic MF term. Reason: Real interaction with the E2 (UFC1) underlying conjugation, but the generic protein binding term is uninformative; captured by the core ufmylation function. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Interacts with UFC1 |
| GO:0071569 protein ufmylation | IMP PMID:29868776 Biallelic UFM1 and UFC1 mutations expand the essential role ... | ACCEPT | Summary: HLD14 disease genetics. The R81C variant decreases UFM1 thioester formation with UBA5/UFC1 and decreases ufmylation, directly implicating UFM1 in the ufmylation process. Core process annotation. Reason: Core ufmylation process supported by disease-variant functional characterization. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt decreased ability to form |
| GO:0005634 nucleus | IDA PMID:28393202 Ufm1 inhibits LPS-induced endothelial cell inflammatory resp... | KEEP AS NON CORE | Summary: Direct nuclear localization of UFM1. Consistent with the documented nucleus/cytoplasm dual localization. The part_of qualifier is unusual for a soluble modifier. Reason: Nuclear localization is supported but non-core relative to UFM1's principal cytoplasmic/ER site of action. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005737 cytoplasm | IDA PMID:28393202 Ufm1 inhibits LPS-induced endothelial cell inflammatory resp... | ACCEPT | Summary: Direct cytoplasmic localization of UFM1, consistent with its primary site of action. The part_of qualifier is unusual for a soluble modifier. Reason: Cytoplasmic localization is well supported and consistent with where ufmylation acts. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Cytoplasm |
| GO:0042308 negative regulation of protein import into nucleus | IMP PMID:28393202 Ufm1 inhibits LPS-induced endothelial cell inflammatory resp... | MARK AS OVER ANNOTATED | Summary: A single low-throughput (CACAO) annotation proposing UFM1 negatively regulates nuclear protein import. This is a narrow, context-specific claim not corroborated by the broader UFM1 literature. Reason: Isolated, context-specific annotation not central to UFM1 biology and not corroborated by the principal ufmylation literature. Supporting Evidence: file:human/UFM1/UFM1-goa.tsv negative regulation of protein import into nucleus |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence/orthology-based ER localization, consistent with UFM1 acting at the ER-bound ribosome where its principal substrate RPL26 is ufmylated. Reason: Reflects UFM1's functionally important ER-associated site of action, though by orthology transfer; non-core compartment annotation. Supporting Evidence: PMID:30626644 tethered to the cytoplasmic surface of the ER |
| GO:0043066 negative regulation of apoptotic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence/orthology-based anti-apoptotic annotation, redundant with the IEA annotation for the same process. Indirect, context-dependent downstream effect. Reason: Indirect downstream phenotype supported only by orthology transfer; not a direct or core function of UFM1. Supporting Evidence: file:human/UFM1/UFM1-goa.tsv negative regulation of apoptotic process |
| GO:1990592 protein K69-linked ufmylation | IDA PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | ACCEPT | Summary: UFM1 can be conjugated as a Lys-linked polymer; Lys-69 is a UFM1-UFM1 linkage site (auto-ufmylation/poly-UFM1 chains), directly demonstrated. A specific molecular aspect of the core ufmylation process. Reason: Specific, experimentally supported ufmylation chain-linkage process directly involving UFM1 (its Lys-69 crosslink), corroborated by the UniProt CROSSLNK feature. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Glycyl lysine isopeptide (Lys-Gly) (interchain with |
| GO:0033146 regulation of intracellular estrogen receptor signaling pathway | IDA PMID:25219498 Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... | KEEP AS NON CORE | Summary: Ufmylation of the substrate ASC1 (TRIP4) regulates ERalpha transactivation in breast cancer. This is a substrate-specific downstream signaling outcome of ufmylation. Reason: Substrate-specific (ASC1) downstream signaling consequence of ufmylation; non-core relative to UFM1's molecular tag role. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Modification of ASC1 by UFM1 is crucial for ERalpha transactivation |
| 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 and vesicle-trafficking disturbance (e.g. thapsigargin), placing ufmylation within the ER-stress response. Genuine downstream process. Reason: Genuine ufmylation-associated process, but downstream of and non-core relative to UFM1's molecular role. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Up-regulated by thapsigargin |
| GO:0005634 nucleus | IDA PMID:15071506 A novel protein-conjugating system for Ufm1, a ubiquitin-fol... | KEEP AS NON CORE | Summary: The founding UFM1 study directly observed nuclear localization. Consistent with the documented nucleus/cytoplasm dual localization. Reason: Supported nuclear localization, but non-core relative to UFM1's principal cytoplasmic/ER site of action. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0005737 cytoplasm | IDA PMID:15071506 A novel protein-conjugating system for Ufm1, a ubiquitin-fol... | ACCEPT | Summary: The founding UFM1 study directly observed cytoplasmic localization, the primary site where the ufmylation cascade operates. Reason: Well-supported cytoplasmic localization consistent with UFM1's site of action. Supporting Evidence: file:human/UFM1/UFM1-uniprot.txt Cytoplasm |
| GO:0071569 protein ufmylation | IDA PMID:15071506 A novel protein-conjugating system for Ufm1, a ubiquitin-fol... | ACCEPT | Summary: The founding study established the UFM1 conjugation system (E1 UBA5, E2 UFC1) and that UFM1 conjugates to target proteins. Direct support for the core ufmylation process. Reason: Core biological process directly demonstrated in the defining UFM1 paper. Supporting Evidence: PMID:15071506 it conjugates to the |
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Download this section (compressed HTML)Q: Beyond RPL26, what is the full repertoire of physiological UFM1 substrates, and how is substrate selection determined by the UFL1/DDRGK1 E3 module?
Q: How do monomeric versus K69-linked poly-UFM1 chains differ in their signaling outputs (e.g. ribosome recycling versus reticulophagy versus the DNA-damage response)?
Q: What is the mechanistic basis by which loss of UFM1 conjugation causes hypomyelinating leukodystrophy and is essential for brain development?
Experiment: Site-specific proteomics (e.g. K-GG-style enrichment adapted for UFM1 remnants) across tissues and stress conditions to define the comprehensive UFMylated proteome beyond RPL26.
Experiment: Reconstitution of the full ER-tethered ufmylation/de-ufmylation cycle in vitro with defined UBA5/UFC1/UFL1/DDRGK1 and 60S ribosomes to dissect how UFM1 conjugation drives 60S recycling.
Experiment: Structure-function analysis of poly-UFM1 chain linkages (K69 vs monomer) using chain-defective UFM1 mutants to test which downstream processes require polymeric versus monomeric ufmylation.
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