UFL1

UniProt ID: O94874
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

UFL1 (E3 UFM1-protein ligase 1; also called Maxer, NLBP, RCAD, KIAA0776) is the E3 ligase of the UFM1 (ufmylation) cascade, which catalyzes covalent attachment of the ubiquitin-like modifier UFM1 to substrate lysines. UFL1 is the catalytic component of the UFM1 ribosome E3 ligase (UREL) complex together with its obligate cofactor DDRGK1/UFBP1 and CDK5RAP3; DDRGK1 tethers the complex to the endoplasmic-reticulum membrane. Acting as a non-canonical scaffold-type E3, UFL1 activates the E2 enzyme UFC1 to transfer UFM1 onto substrates. Its principal physiological substrate is the 60S ribosomal protein RPL26/uL24, where mono-ufmylation of RPL26 on ER-bound ribosomes weakens the junction between post-termination or stalled 60S subunits and SEC61 translocons, promoting release and recycling of the large subunit and supporting ribosome-associated protein quality control. UFL1 also drives reticulophagy (ER-phagy) and the response to ER stress through ufmylation of ER proteins such as CYB5R3 and RPN1, participates in the DNA-damage response (ufmylating histone H4 and MRE11 to promote ATM activation), and ufmylates additional substrates including TP53/p53, PD-L1 and PD-1, contributing to protein stabilization and immune regulation. UFL1 acts mainly at the ER membrane but is also recruited to sites of DNA damage in the nucleus.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0071568 UFM1 transferase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: UFM1 transferase activity is a near-synonymous description of UFL1's E3 UFM1-ligase activity (transfer of UFM1 to substrate).
Reason: UFL1 is the E3 that mediates UFM1 transfer to substrates; this MF term captures that activity, with GO:0061666 (UFM1 ligase activity) being the most precise E3-step term.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0061709 reticulophagy
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: UFL1-mediated ufmylation drives reticulophagy (ER-phagy).
Reason: A genuine downstream process of ER ufmylation; non-core relative to the E3 ligase activity.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Involved in reticulophagy in response to endoplasmic reticulum stress
GO:0005789 endoplasmic reticulum membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: UFL1 acts at the ER membrane as part of the DDRGK1-tethered UREL complex.
Reason: ER membrane is the principal site of UFL1 catalytic action.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0034976 response to endoplasmic reticulum stress
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: UFL1-mediated ufmylation functions in the ER stress response.
Reason: Valid pathway context; non-core relative to the E3 ligase activity.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Ufmylation in response to endoplasmic reticulum stress
GO:0005634 nucleus
IEA
GO_REF:0000044 		ACCEPT
Summary: UFL1 is recruited to the nucleus/sites of DNA damage; nuclear localization is documented experimentally.
Reason: Consistent with UFL1's DNA-damage role at double-strand breaks.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Nucleus
GO:0005694 chromosome
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: UFL1 localizes to chromosomes/sites of double-strand breaks during the DNA-damage response.
Reason: Documented chromatin localization linked to the DNA-damage role; non-core relative to the principal ER-membrane site of action.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Chromosome
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: ER membrane localization, the principal compartment of UFL1.
Reason: Correct compartment; corroborated by experimental evidence.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005829 cytosol
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Cytosolic localization, consistent with UFL1's cytoplasm-facing activity.
Reason: Documented cytoplasmic pool; the principal site of action is the ER membrane.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Cytoplasm, cytosol
GO:0061666 UFM1 ligase activity
IEA
GO_REF:0000002 		ACCEPT
Summary: UFM1 ligase (E3) activity is the core molecular function of UFL1; this electronic annotation is corroborated by extensive direct experimental evidence.
Reason: UFL1 is the E3 ligase of the ufmylation cascade; this is its core MF.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0071569 protein ufmylation
IEA
GO_REF:0000002 		ACCEPT
Summary: UFL1 is the E3 of protein ufmylation.
Reason: Core process annotation for the E3 ligase.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: Binary interactome interaction. Bare protein binding is uninformative.
Reason: Records a real interaction but the term is uninformative; core MF is UFM1 ligase activity.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex affinity-purification interactions. Bare protein binding is uninformative.
Reason: Real interactions but uninformative term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781
GO:0005515 protein binding
IPI
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		KEEP AS NON CORE
Summary: Interactions with UREL-complex partners. Bare term uninformative.
Reason: Real cascade interactions; non-core under generic term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:37595036
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. Bare protein binding is uninformative.
Reason: Real interaction record but uninformative term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054
GO:0005737 cytoplasm
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cytoplasmic localization (electronic).
Reason: Documented cytoplasmic pool; principal site is the ER membrane.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Cytoplasm, cytosol
GO:0010508 positive regulation of autophagy
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: UFL1 promotes autophagy/reticulophagy via ER ufmylation, inferred electronically.
Reason: Plausible downstream process; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Involved in reticulophagy in response to endoplasmic reticulum stress
GO:0030218 erythrocyte differentiation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Role in erythroid/hematopoietic differentiation inferred by similarity.
Reason: Plausible by orthology; downstream developmental role, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Required for hematopoietic stem cell function and hematopoiesis
GO:0034976 response to endoplasmic reticulum stress
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: ER stress response (electronic), corroborated experimentally.
Reason: Valid pathway context; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Ufmylation in response to endoplasmic reticulum stress
GO:0043005 neuron projection
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Neuron-projection localization inferred electronically from the ortholog.
Reason: Electronically inferred; peripheral to the core ER-membrane site of action.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0043005 neuron projection cellular_component
GO:0050868 negative regulation of T cell activation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: UFL1 negatively regulates T-cell activation via ufmylation/stabilization of PD-1, inferred electronically and shown experimentally.
Reason: Documented immune-regulatory role; downstream, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1
GO:0060218 hematopoietic stem cell differentiation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Role in hematopoietic stem cell function inferred by similarity.
Reason: Plausible by orthology; downstream developmental role, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Required for hematopoietic stem cell function and hematopoiesis
GO:0050821 protein stabilization
IDA
PMID:32807901
UFMylation maintains tumour suppressor p53 stability by anta... 		KEEP AS NON CORE
Summary: UFL1-mediated ufmylation of TP53/p53 stabilizes it by antagonizing its ubiquitination.
Reason: A documented substrate-specific stabilization effect; downstream of the E3 activity, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Mediates ufmylation of TP53/p53, promoting its stability
GO:0005783 endoplasmic reticulum
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct (HPA) ER localization.
Reason: IDA-supported ER localization consistent with site of action.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005783 endoplasmic reticulum cellular_component ECO:0000314 IDA GO_REF:0000052
GO:0005694 chromosome
EXP
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		KEEP AS NON CORE
Summary: UFL1 localizes to chromatin/double-strand-break sites during the DNA-damage response (histone H4 ufmylation/ATM activation).
Reason: Documented DNA-damage-associated localization; non-core relative to the principal ER-membrane site.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
recruited to double-strand break sites following DNA damage
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		ACCEPT
Summary: Experimental ER membrane localization from the paper identifying UFL1 as the UFM1 E3 ligase.
Reason: Direct evidence for the principal compartment.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:20164180
A novel LZAP-binding protein, NLBP, inhibits cell invasion. 		ACCEPT
Summary: Experimental ER membrane localization (NLBP/UFL1).
Reason: Direct evidence for the principal compartment.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:20228063
A novel C53/LZAP-interacting protein regulates stability of ... 		ACCEPT
Summary: Experimental ER membrane localization (RCAD/UFL1).
Reason: Direct evidence for the principal compartment.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0071569 protein ufmylation
IDA
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: UFL1 is the E3 mediating ufmylation in the scaffold-type complex.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:1990234 transferase complex
IPI
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: UFL1 is the catalytic component of the UREL transferase complex.
Reason: UFL1 is a bona fide subunit of the UFM1 E3 ligase (transferase) complex.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Catalytic component of the UFM1 ribosome E3 ligase (UREL) complex
GO:0005783 endoplasmic reticulum
IDA
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostas... 		ACCEPT
Summary: UFL1 acts at the ER (HRD1 ufmylation study).
Reason: Direct evidence for the site of action.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0006974 DNA damage response
IDA
PMID:32807901
UFMylation maintains tumour suppressor p53 stability by anta... 		KEEP AS NON CORE
Summary: UFL1 participates in the DNA-damage response (p53 stabilization context).
Reason: A genuine but downstream role of UFL1's ufmylation activity; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Also involved in the response to DNA damage
GO:0061666 UFM1 ligase activity
IDA
PMID:32807901
UFMylation maintains tumour suppressor p53 stability by anta... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of p53).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0061666 UFM1 ligase activity
IDA
PMID:35753586
P4HB UFMylation regulates mitochondrial function and oxidati... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of P4HB).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0061666 UFM1 ligase activity
IDA
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostas... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of HRD1/SYVN1).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0071569 protein ufmylation
IDA
PMID:32807901
UFMylation maintains tumour suppressor p53 stability by anta... 		ACCEPT
Summary: UFL1 ufmylates p53.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Mediates ufmylation of TP53/p53, promoting its stability
GO:0071569 protein ufmylation
IDA
PMID:35753586
P4HB UFMylation regulates mitochondrial function and oxidati... 		ACCEPT
Summary: UFL1 ufmylates P4HB.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0071569 protein ufmylation
IDA
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostas... 		ACCEPT
Summary: UFL1 ufmylates HRD1/SYVN1.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SYVN1/HRD1
GO:0002841 negative regulation of T cell mediated immune response to tumor cell
IDA
PMID:38377992
UFL1 ablation in T cells suppresses PD-1 UFMylation to enhan... 		KEEP AS NON CORE
Summary: UFL1 ufmylates/stabilizes PD-1, suppressing anti-tumor T-cell immunity.
Reason: A documented immune-regulatory role downstream of the E3 activity; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1
GO:0050821 protein stabilization
IDA
PMID:38377992
UFL1 ablation in T cells suppresses PD-1 UFMylation to enhan... 		KEEP AS NON CORE
Summary: UFL1 ufmylation stabilizes PD-1.
Reason: Substrate-specific stabilization downstream of the E3 activity; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
mediating ufmylation and stabilization of PDCD1/PD-1
GO:0050868 negative regulation of T cell activation
IDA
PMID:38377992
UFL1 ablation in T cells suppresses PD-1 UFMylation to enhan... 		KEEP AS NON CORE
Summary: UFL1 negatively regulates T-cell activation via PD-1 ufmylation.
Reason: Documented immune-regulatory role; downstream, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1
GO:0061666 UFM1 ligase activity
IDA
PMID:36893266
Dysregulation of PD-L1 by UFMylation imparts tumor immune ev... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of PD-L1/CD274).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
CD274/PD-L1
GO:0061666 UFM1 ligase activity
IDA
PMID:38377992
UFL1 ablation in T cells suppresses PD-1 UFMylation to enhan... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of PD-1/PDCD1).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
PDCD1/PD-1
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		ACCEPT
Summary: UFL1 acts at the ER membrane within UREL (CYB5R3/ER-phagy study).
Reason: Direct evidence for the site of action.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0045732 positive regulation of protein catabolic process
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		KEEP AS NON CORE
Summary: UFL1-mediated ufmylation promotes lysosomal degradation of ufmylated ER proteins (reticulophagy).
Reason: Downstream consequence of ER ufmylation; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
thereby promoting lysosomal degradation of ufmylated proteins
GO:0061666 UFM1 ligase activity
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of CYB5R3).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0061666 UFM1 ligase activity
IMP
PMID:37036982
RPL26/uL24 UFMylation is essential for ribosome-associated q... 		ACCEPT
Summary: Functional evidence for UFL1 UFM1 ligase activity in ER ribosome-associated quality control (RPL26 ufmylation).
Reason: Direct functional support for the core E3 ligase activity.
Supporting Evidence:
PMID:37036982
RQC-dependent degradation of ER-APs strictly requires conjugation of the
GO:0061666 UFM1 ligase activity
IDA
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity in the mechanistic UREL study.
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0071569 protein ufmylation
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		ACCEPT
Summary: UFL1 ufmylates CYB5R3.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0071569 protein ufmylation
IMP
PMID:37036982
RPL26/uL24 UFMylation is essential for ribosome-associated q... 		ACCEPT
Summary: UFL1 required for RPL26 ufmylation in ER-RQC.
Reason: Functional evidence for the core process.
Supporting Evidence:
PMID:37036982
UFMylation of translocon-bound 60S subunits modulates the RTJ
GO:0071569 protein ufmylation
IDA
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		ACCEPT
Summary: UFL1 mediates ufmylation in the mechanistic UREL study.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0072344 rescue of stalled cytosolic ribosome
IMP
PMID:37036982
RPL26/uL24 UFMylation is essential for ribosome-associated q... 		ACCEPT
Summary: UFL1, via RPL26 ufmylation, contributes to release/recycling of stalled 60S ribosomes at the ER, supporting ribosome-associated quality control. This is the major biological process of UFL1.
Reason: A core physiological role of UFL1 ufmylation - ribosome recycling/RQC at the ER-translocon junction.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase co... 		ACCEPT
Summary: UFL1 contributes to ribosome recycling/RQC via RPL26 ufmylation.
Reason: Core physiological role of UFL1 ufmylation.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
GO:0140501 positive regulation of reticulophagy
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		KEEP AS NON CORE
Summary: UFL1-mediated ufmylation positively regulates reticulophagy.
Reason: Valid downstream process; non-core relative to the E3 activity.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Involved in reticulophagy in response to endoplasmic reticulum stress
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: UFL1 acts at the ER membrane within the UREL-60S complex.
Reason: Direct structural evidence for the site of action.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: UFL1 acts at the ER membrane within the UREL-60S complex.
Reason: Direct structural evidence for the site of action.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0032790 ribosome disassembly
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		KEEP AS NON CORE
Summary: UFL1-mediated RPL26 ufmylation promotes release/dissociation of 60S from the ER translocon.
Reason: Genuine role in 60S release/recycling; captured as downstream process, non-core relative to the E3 MF.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
promoting release and recycling of the large ribosomal subunit
GO:0032790 ribosome disassembly
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		KEEP AS NON CORE
Summary: UFL1-mediated RPL26 ufmylation promotes 60S release from the ER translocon.
Reason: Genuine role in 60S release/recycling; downstream process, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
promoting release and recycling of the large ribosomal subunit
GO:0061666 UFM1 ligase activity
IDA
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylatio... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (RPL26 is the principal target).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation
GO:0061666 UFM1 ligase activity
IDA
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates pro... 		ACCEPT
Summary: UFL1 acts as a non-canonical scaffold-type E3, activating UFC1 to transfer UFM1.
Reason: Direct mechanistic support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0061666 UFM1 ligase activity
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: Structural/functional evidence for UFL1 E3 ligase activity within the UREL-60S complex.
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0061666 UFM1 ligase activity
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: Structural evidence for UFL1 E3 ligase activity in the UREL-60S complex.
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
PMID:38383789
the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26
GO:0071569 protein ufmylation
IDA
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylatio... 		ACCEPT
Summary: UFL1 mediates ufmylation; RPL26 is the principal target.
Reason: Direct evidence for the core process.
Supporting Evidence:
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation
GO:0071569 protein ufmylation
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: UFL1 mediates RPL26 ufmylation in the UREL-60S complex.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0071569 protein ufmylation
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: UFL1 mediates RPL26 ufmylation in the UREL-60S complex.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: UFL1, via RPL26 ufmylation, contributes to release/recycling of stalled 60S ribosomes at the ER.
Reason: Core physiological role of UFL1 ufmylation (ribosome recycling/RQC).
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes fro... 		ACCEPT
Summary: UFL1, via RPL26 ufmylation, contributes to release/recycling of stalled 60S ribosomes from the ER translocon.
Reason: Core physiological role of UFL1 ufmylation (ribosome recycling/RQC).
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
promoting release and recycling of the large ribosomal subunit
GO:0006974 DNA damage response
IDA
PMID:30783677
MRE11 UFMylation promotes ATM activation. 		KEEP AS NON CORE
Summary: UFL1 ufmylates MRE11 to promote ATM activation in the DNA-damage response.
Reason: A genuine but downstream role of UFL1's ufmylation activity; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
mediates monoufmylation of histone H4 and ufmylation of MRE11
GO:0061666 UFM1 ligase activity
IDA
PMID:30783677
MRE11 UFMylation promotes ATM activation. 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (ufmylation of MRE11).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
ufmylation of MRE11
GO:0005741 mitochondrial outer membrane
IDA
PMID:20164180
A novel LZAP-binding protein, NLBP, inhibits cell invasion. 		MARK AS OVER ANNOTATED
Summary: A reported mitochondrial-outer-membrane localization; UFL1's principal and best-supported site of action is the ER membrane, and this localization is not central to its function.
Reason: An isolated localization claim at odds with the extensive evidence for ER-membrane action; likely peripheral or context-specific.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005741 mitochondrial outer membrane cellular_component ECO:0000314 IDA PMID:20164180
GO:0000077 DNA damage checkpoint signaling
IDA
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		KEEP AS NON CORE
Summary: UFL1 promotes ATM activation (a DNA-damage checkpoint kinase) via histone H4 ufmylation.
Reason: A documented downstream signaling role of UFL1 ufmylation; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
mediates monoufmylation of histone H4
GO:0005515 protein binding
IPI
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		KEEP AS NON CORE
Summary: Interaction with NBN/UFC1 in the histone H4 ufmylation/ATM study. Bare term uninformative.
Reason: Real interactions (including cascade partner UFC1); non-core under generic term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:30886146
GO:0005515 protein binding
IPI
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: Interaction with DDRGK1 in the ER-phagy screen. Bare term uninformative.
Reason: Real cascade interaction; non-core under generic term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32160526
GO:0005634 nucleus
IDA
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		ACCEPT
Summary: Direct nuclear localization during the DNA-damage response.
Reason: Direct evidence for nuclear localization linked to UFL1's DNA-damage role.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Nucleus
GO:0005737 cytoplasm
IDA
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		KEEP AS NON CORE
Summary: Direct cytoplasmic localization.
Reason: Documented cytoplasmic pool; principal site is the ER membrane.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Cytoplasm, cytosol
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		ACCEPT
Summary: ER membrane localization from the ER-phagy screen.
Reason: Direct evidence for the principal compartment.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0010508 positive regulation of autophagy
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Positive regulation of autophagy/reticulophagy transferred from ortholog.
Reason: Plausible by orthology; downstream process, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Involved in reticulophagy in response to endoplasmic reticulum stress
GO:0019901 protein kinase binding
IPI
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		KEEP AS NON CORE
Summary: UFL1 binds the protein kinase ATM (and is phosphorylated by it) in the DNA-damage response.
Reason: A real, specific protein-kinase interaction underlying the DNA-damage role; informative but non-core relative to the E3 ligase activity.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Phosphorylated at Ser-462 by ATM
GO:0030218 erythrocyte differentiation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Erythroid differentiation role transferred from ortholog.
Reason: Plausible by orthology; downstream developmental role, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Required for hematopoietic stem cell function and hematopoiesis
GO:0034976 response to endoplasmic reticulum stress
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: UFL1 functions in the ER stress response.
Reason: Valid pathway context; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Ufmylation in response to endoplasmic reticulum stress
GO:0035861 site of double-strand break
IDA
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		KEEP AS NON CORE
Summary: UFL1 is recruited to double-strand-break sites during the DNA-damage response.
Reason: Documented DNA-damage-associated localization; non-core relative to the principal ER-membrane site.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
recruited to double-strand break sites following DNA damage
GO:0043122 regulation of canonical NF-kappaB signal transduction
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: NF-kappaB regulatory role transferred from ortholog (UFL1/DDRGK1 axis).
Reason: Plausible by orthology; downstream signaling role, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0043122 regulation of canonical NF-kappaB signal transduction biological_process ECO:0000250 ISS GO_REF:0000024
GO:0050727 regulation of inflammatory response
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Inflammatory-response regulation transferred from ortholog.
Reason: Plausible by orthology; downstream, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
inflammatory response
GO:0060218 hematopoietic stem cell differentiation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Hematopoietic stem cell differentiation transferred from ortholog.
Reason: Plausible by orthology; downstream developmental role, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Required for hematopoietic stem cell function and hematopoiesis
GO:0061666 UFM1 ligase activity
IDA
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity (histone H4 ufmylation).
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
mediates monoufmylation of histone H4
GO:0061666 UFM1 ligase activity
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		ACCEPT
Summary: Direct evidence of UFL1 UFM1 ligase activity in the ER-phagy context.
Reason: Direct support for the core E3 ligase molecular function.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0061709 reticulophagy
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: UFL1 drives reticulophagy via ER ufmylation.
Reason: Valid downstream process; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Involved in reticulophagy in response to endoplasmic reticulum stress
GO:0071569 protein ufmylation
IDA
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation. 		ACCEPT
Summary: UFL1 ufmylates histone H4.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
mediates monoufmylation of histone H4
GO:0071569 protein ufmylation
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		ACCEPT
Summary: UFL1 mediates ufmylation in the ER-phagy context.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:1903895 negative regulation of IRE1-mediated unfolded protein response
IDA
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitoch... 		KEEP AS NON CORE
Summary: UFL1/UREL-dependent ufmylation negatively regulates the IRE1 arm of the UPR (via DDRGK1-IRE1-alpha).
Reason: Documented signaling role downstream of ufmylation; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Ufmylation-dependent reticulophagy inhibits the unfolded protein response
GO:0061666 UFM1 ligase activity
IDA
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		ACCEPT
Summary: The founding paper identifying UFL1 as the E3 ligase of the UFM1 system, with catalytic activity demonstrated.
Reason: Original direct demonstration of the core E3 UFM1 ligase activity.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0032991 protein-containing complex
IDA
PMID:20531390
Suppression of the novel ER protein Maxer by mutant ataxin-1... 		KEEP AS NON CORE
Summary: UFL1 (Maxer) is part of an ER protein complex; more specifically the UREL complex.
Reason: A generic complex-membership term; the specific and informative term is the UREL transferase complex.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0032991 protein-containing complex cellular_component ECO:0000314 IDA PMID:20531390
GO:0001649 osteoblast differentiation
HDA
PMID:16210410
Differential expression profiling of membrane proteins by qu... 		KEEP AS NON CORE
Summary: From a membrane-proteomics differentiation study; an HDA association not central to UFL1's defined function.
Reason: High-throughput association of uncertain functional relevance; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0001649 osteoblast differentiation biological_process ECO:0007005 HDA PMID:16210410
GO:0016020 membrane
HDA
PMID:16210410
Differential expression profiling of membrane proteins by qu... 		KEEP AS NON CORE
Summary: Membrane association from proteomics; consistent with UFL1's ER-membrane localization but non-specific.
Reason: Generic membrane term; the specific compartment is the ER membrane.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:1990592 protein K69-linked ufmylation
IDA
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: UFL1 mediates ufmylation including K69-linked UFM1 chains.
Reason: Specific chain-linkage sub-aspect of ufmylation; narrow process annotation.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:1990592 protein K69-linked ufmylation biological_process ECO:0000314 IDA PMID:25219498
GO:0005515 protein binding
IPI
PMID:20228063
A novel C53/LZAP-interacting protein regulates stability of ... 		KEEP AS NON CORE
Summary: Interaction with CDK5RAP3/DDRGK1 (RCAD study). Bare term uninformative.
Reason: Real cascade interactions; non-core under generic term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20228063
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: UFL1 ufmylates TRIP4/ASC1, affecting ERalpha transactivation.
Reason: A specialized signaling role downstream of ufmylation; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription
GO:0005515 protein binding
IPI
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: Interaction with DDRGK1/TRIP4 (ASC1/ufmylation study). Bare term uninformative.
Reason: Real cascade-relevant interactions; non-core under generic term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25219498
GO:0005783 endoplasmic reticulum
IDA
PMID:20531390
Suppression of the novel ER protein Maxer by mutant ataxin-1... 		ACCEPT
Summary: ER localization (Maxer/UFL1).
Reason: Direct evidence for the principal compartment.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:20531390
Suppression of the novel ER protein Maxer by mutant ataxin-1... 		ACCEPT
Summary: ER membrane localization (Maxer/UFL1).
Reason: Direct evidence for the principal compartment.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0008284 positive regulation of cell population proliferation
IMP
PMID:20531390
Suppression of the novel ER protein Maxer by mutant ataxin-1... 		KEEP AS NON CORE
Summary: Effect on cell proliferation in the Maxer study.
Reason: Downstream cellular phenotype; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0008284 positive regulation of cell population proliferation biological_process ECO:0000315 IMP PMID:20531390
GO:0032880 regulation of protein localization
IMP
PMID:20531390
Suppression of the novel ER protein Maxer by mutant ataxin-1... 		KEEP AS NON CORE
Summary: UFL1 affects protein localization in the Maxer study.
Reason: Downstream effect; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0032880 regulation of protein localization biological_process ECO:0000315 IMP PMID:20531390
GO:0032434 regulation of proteasomal ubiquitin-dependent protein catabolic process
IMP
PMID:20228063
A novel C53/LZAP-interacting protein regulates stability of ... 		KEEP AS NON CORE
Summary: UFL1 regulates proteasomal degradation (protects CDK5RAP3/itself from ubiquitination).
Reason: Downstream effect on protein turnover; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation
GO:0034976 response to endoplasmic reticulum stress
IDA
PMID:23152784
Transcriptional regulation of the Ufm1 conjugation system in... 		KEEP AS NON CORE
Summary: UFL1 is up-regulated by ER stress (thapsigargin) and functions in ER homeostasis.
Reason: Valid pathway context; non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Up-regulated by thapsigargin
GO:0071569 protein ufmylation
IMP
PMID:23152784
Transcriptional regulation of the Ufm1 conjugation system in... 		ACCEPT
Summary: UFL1 is part of the UFM1 conjugation system implicated in ER homeostasis.
Reason: Supports the core process annotation.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation
GO:0005515 protein binding
IPI
PMID:20164180
A novel LZAP-binding protein, NLBP, inhibits cell invasion. 		KEEP AS NON CORE
Summary: Interaction with CDK5RAP3/LZAP and RELA (NLBP study). Bare term uninformative.
Reason: Real interactions (including cascade partner CDK5RAP3); non-core under generic term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20164180
GO:0031397 negative regulation of protein ubiquitination
IDA
PMID:20164180
A novel LZAP-binding protein, NLBP, inhibits cell invasion. 		KEEP AS NON CORE
Summary: UFL1 (NLBP) interaction with CDK5RAP3 protects against ubiquitination/degradation.
Reason: A documented effect on partner stability; downstream, non-core.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation
GO:0005737 cytoplasm
IDA
PMID:20164180
A novel LZAP-binding protein, NLBP, inhibits cell invasion. 		KEEP AS NON CORE
Summary: Cytoplasmic localization (NLBP/UFL1).
Reason: Documented cytoplasmic pool; principal site is the ER membrane.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
Cytoplasm, cytosol
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 DDRGK1 and UFC1 in the founding UFM1 E3 ligase paper. Bare term uninformative.
Reason: Real cascade interactions; non-core under generic term.
Supporting Evidence:
file:human/UFL1/UFL1-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:20018847
GO:0005783 endoplasmic reticulum
IDA
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		ACCEPT
Summary: ER localization from the founding UFM1 E3 ligase paper.
Reason: Direct evidence for the principal compartment.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0071569 protein ufmylation
IDA
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system. 		ACCEPT
Summary: Founding demonstration that UFL1 is the E3 of ufmylation.
Reason: Direct evidence for the core process.
Supporting Evidence:
file:human/UFL1/UFL1-uniprot.txt
E3 protein ligase that mediates ufmylation

Core Functions

E3 UFM1-protein ligase, the catalytic component of the UFM1 ribosome E3 ligase (UREL) complex (with cofactor DDRGK1 and CDK5RAP3), that acts as a non-canonical scaffold-type E3 to activate the E2 UFC1 and catalyze transfer of UFM1 onto substrate lysines.

Molecular Function:
UFM1 ligase activity
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • file:human/UFL1/UFL1-uniprot.txt
    E3 protein ligase that mediates ufmylation
  • PMID:30626644
    Ribosomal protein RPL26 is the principal target of UFMylation

Mediates mono-ufmylation of the 60S ribosomal protein RPL26/uL24 on ER-bound ribosomes, weakening the 60S-SEC61 junction to promote release and recycling of post-termination/stalled large ribosomal subunits, thereby supporting ribosome-associated protein quality control at the ER.

Molecular Function:
UFM1 ligase activity
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • file:human/UFL1/UFL1-uniprot.txt
    plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome
  • PMID:37036982
    UFMylation of translocon-bound 60S subunits modulates the RTJ

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
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:0000044
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
PMID:16210410
Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation.
PMID:20018847
A novel type of E3 ligase for the Ufm1 conjugation system.
  • UFL1 is the E3 ligase of the UFM1 conjugation system and interacts with DDRGK1 and the E2 UFC1.
PMID:20164180
A novel LZAP-binding protein, NLBP, inhibits cell invasion.
  • UFL1/NLBP interacts with CDK5RAP3/LZAP and RELA and protects partners from ubiquitin-mediated degradation.
PMID:20228063
A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling.
  • UFL1/RCAD interacts with CDK5RAP3 and regulates stability of CDK5RAP3 and DDRGK1, modulating NF-kappaB.
PMID:20531390
Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity.
  • UFL1/Maxer is an ER protein whose suppression contributes to non-cell-autonomous toxicity.
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 (including UFL1) is up-regulated upon ER stress.
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
  • UFL1 ufmylates TRIP4/ASC1, contributing to ERalpha transactivation.
PMID:30626644
Ribosomal protein RPL26 is the principal target of UFMylation.
  • RPL26 is the principal cellular target of UFMylation.
PMID:30783677
MRE11 UFMylation promotes ATM activation.
  • UFL1 ufmylates MRE11 to promote ATM activation in the DNA-damage response.
PMID:30886146
UFL1 promotes histone H4 ufmylation and ATM activation.
  • UFL1 is recruited to double-strand breaks via NBN, ufmylates histone H4, and promotes ATM activation.
PMID:32160526
A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-Resident UFMylation.
  • UFL1 and ER-resident UFMylation drive ER-phagy and regulate the IRE1 UPR.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32807901
UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.
  • UFL1-mediated ufmylation of TP53/p53 stabilizes p53 by antagonizing its ubiquitination.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35753586
P4HB UFMylation regulates mitochondrial function and oxidative stress.
  • UFL1 ufmylates P4HB, regulating mitochondrial function and oxidative stress.
PMID:36121123
A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
  • UFL1/DDRGK1 forms a non-canonical scaffold-type E3 (UREL) that activates the E2 UFC1 to ufmylate substrate.
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
  • UFL1/UREL ufmylates CYB5R3 to drive ER-phagy.
PMID:36893266
Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target.
  • UFL1 ufmylates CD274/PD-L1, affecting tumor immune evasion.
PMID:37036982
RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.
  • UFL1-mediated RPL26 ufmylation is required for ribosome-associated quality control at the ER.
PMID:37595036
Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control.
  • UFL1, within UREL, mediates RPL26 ufmylation supporting ribosome-associated protein quality control.
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
  • UFL1 ufmylates SYVN1/HRD1, regulating ER homeostasis.
PMID:38377992
UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity.
  • UFL1 ufmylates and stabilizes PDCD1/PD-1, negatively regulating anti-tumor T-cell immunity.
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.
  • The UFL1/DDRGK1/CDK5RAP3 (UREL) complex ufmylates RPL26 to promote recycling of 60S ribosomal subunits from the ER.
PMID:38383789
The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
  • UREL (UFL1/DDRGK1/CDK5RAP3) wraps around the 60S subunit, ufmylates RPL26, and releases/recycles ribosomes from ER translocons.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.

Suggested Questions for Experts

Q: How is UFL1 substrate selectivity determined across its diverse substrates (RPL26, histone H4, MRE11, p53, PD-1/PD-L1, CYB5R3) - is it driven by DDRGK1/CDK5RAP3 adaptors, localization, or post-translational regulation?

Q: Is the reported mitochondrial-outer-membrane localization of UFL1 a genuine functional pool or carryover from ER-mitochondria contact sites?

Q: How does ATM-mediated phosphorylation of UFL1 at Ser-462 mechanistically enhance its ligase activity in the DNA-damage response?

Suggested Experiments

Experiment: Substrate-trapping or proximity-labeling proteomics of catalytically active versus inactive UFL1 across ER-stress, DNA-damage and basal conditions to define context-dependent substrate repertoires.

Experiment: Reconstitute the UREL-60S complex with purified UFL1/DDRGK1/CDK5RAP3 and UFC1 to measure how each subunit and the ATM-phosphorylation site contribute to RPL26 ufmylation and 60S release from SEC61.

Experiment: Separation-of-function UFL1 alleles tested in ER-RQC reporter, reticulophagy, and DNA-damage (ATM activation) assays to determine whether a single catalytic activity underlies all phenotypes.

πŸ“š Additional Documentation

Notes

(UFL1-notes.md)

UFL1 (E3 UFM1-protein ligase 1) β€” research notes

UniProt: O94874 (UFL1_HUMAN), 794 aa. HGNC:23039. Chromosome 6. Synonyms: Maxer, NLBP, RCAD, KIAA0776.

Step in the cascade

UFL1 is the E3 ligase of the UFM1 (ufmylation) cascade (E1=UBA5, E2=UFC1, E3=UFL1).
EC=2.3.2.- (transferase). It is the catalytic component of the UREL complex (UFL1 + DDRGK1 + CDK5RAP3).
- UniProt FUNCTION: "E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins."
- Non-canonical scaffold-type E3 that activates the E2 UFC1 for aminolysis PMID:36121123.
- DDRGK1 tethers UREL to the ER membrane; CDK5RAP3 is the third subunit.

Core biology

  • Principal substrate RPL26/uL24 on 60S ribosomes PMID:30626644.
  • Ribosome recycling / ER-RQC: mono-ufmylation of RPL26 weakens the 60S–SEC61 junction, promoting release/recycling of post-termination or stalled 60S subunits [PMID:38383785; PMID:38383789; PMID:37036982 "UFMylation of translocon-bound 60S subunits modulates the RTJ"]. Core BP = GO:0072344 rescue of stalled ribosome (recycling).
  • Reticulophagy / ER stress: ufmylates CYB5R3 PMID:36543799, RPN1; drives ER-phagy.
  • DNA-damage response: recruited to DSBs via NBN; ufmylates histone H4 and MRE11 to promote ATM activation [PMID:30886146; PMID:30783677]. Phosphorylated at Ser-462 by ATM (positive feedback).
  • Other substrates: TP53/p53 (stabilization) PMID:32807901; PD-L1/CD274 PMID:36893266; PD-1/PDCD1 (immune regulation) PMID:38377992; P4HB PMID:35753586; SYVN1/HRD1 PMID:37795761; TRIP4/ASC1 PMID:25219498.

Localization

Principal site: ER membrane (extensive EXP/IDA evidence). Also cytoplasm/cytosol, nucleus and chromosome (DNA-damage). Mitochondrial outer membrane (PMID:20164180, single IDA) is at odds with the dominant ER picture β€” marked over-annotation.

Core function conclusion

Core MF: GO:0061666 UFM1 ligase activity (E3). Core BP: protein ufmylation (RPL26) supporting 60S recycling / ER-RQC. Many other roles (DNA damage, immune, reticulophagy, transcription) are downstream/non-core.

Pn Notes

(UFL1-pn-notes.md)

UFL1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O94874
  • 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: UFL1 (E3 UFM1-protein ligase 1; also called Maxer, NLBP, RCAD, KIAA0776) is the E3 ligase of the UFM1 (ufmylation) cascade, which catalyzes covalent attachment of the ubiquitin-like modifier UFM1 to substrate lysines. UFL1 is the catalytic component of the UFM1 ribosome E3 ligase (UREL) complex together with its obligate cofactor DDRGK1/UFBP1 and CDK5RAP3; DDRGK1 tethers the complex to the endoplasmic-reticulum membrane. Acting as a non-canonical scaffold-type E3, UFL1 activates the E2 enzyme UFC1 to transfer UFM1 onto substrates. Its principal physiological substrate is the 60S ribosomal protein RPL26/uL24, where mono-ufmylation of RPL26 on ER-bound ribosomes weakens the junction between post-termination or stalled 60S subunits and SEC61 translocons, promoting release and recycling of the large subunit and supporting ribosome-associated protein quality control. UFL1 also drives reticulophagy (ER-phagy) and the response to ER stress through ufmylation of ER proteins such as CYB5R3 and RPN1, participates in the DNA-damage response (ufmylating histone H4 and MRE11 to promote ATM activation), and ufmylates additional substrates including TP53/p53, PD-L1 and PD-1, contributing to protein stabilization and immune regulation. UFL1 acts mainly at the ER membrane but is also recruited to sites of DNA damage in the nucleus.
  • Existing/core annotation action counts: ACCEPT: 54; KEEP_AS_NON_CORE: 55; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Strong. Notes/review/PN agree UFL1 is the UFM1 E3 (UREL: UFL1+DDRGK1+CDK5RAP3; scaffold-type E3 activating UFC1; principal substrate RPL26 β†’ 60S recycling). Review ACCEPTs GO:0061666 (UFM1 ligase activity, IDA x16), GO:0071568, GO:0071569, ER membrane; downstream DNA-damage/immune/ERphagy roles KEEP_AS_NON_CORE. No contradictions.
  • PN story / NEW pressure: All PN assertions captured. GO:0006515 (verified) projected new_to_goa via RQC group is broad; UFL1's RQC role = ufmylation-driven 60S recycling (GO:0071569 annotated; review core_function explicitly describes RPL26β†’recycling). Conclusion: already captured; GO:0006515 over-reaches as a direct UFL1 term. (Note: the more specific GO:0072344 rescue-of-stalled-ribosome appears 4x in UFL1 GOA, a better fit than GO:0006515 if any RQC process were to be added.)
  • Evidence alignment: PN E3 row cites PMID:20018847 (shared β€” review uses it 7x, in GOA as IDA for GO:0061666), plus 25852645 and 20368332 (not in review; family/review citations). Good core-evidence overlap on the E3-ligase identification paper.
  • Verdict: Consistent and complete; PN E3/UFMylation/ERphagy story fully captured by GO:0061666 + GO:0071569. GO:0006515 broader than UFL1's already-annotated GO:0072344/GO:0071569 β€” not warranted as a direct add.

Full Consistency Review

  • UniProt: O94874 Β· batch: proteostasis-batch-2026-06-07c Β· review status: complete (core MF GO:0061666; large annotation set triaged)
  • PN placement: Translation|Cytosolic translation|Ribosome-associated QC|UFMylation; ALP|...|ERphagy|UFMylation of ER proteins; UPS|E3 ubiquitin and UBL ligases|UBL modifiers|UFMylation ; PN-node mapping: UFMylation typeβ†’GO:0071569; ERphagyβ†’GO:0061709; E3 classβ†’GO:0061630 (context only); E3 UBL-modifier typeβ†’no_mapping.
  • Consistency: Strong. Notes/review/PN agree UFL1 is the UFM1 E3 (UREL: UFL1+DDRGK1+CDK5RAP3; scaffold-type E3 activating UFC1; principal substrate RPL26 β†’ 60S recycling). Review ACCEPTs GO:0061666 (UFM1 ligase activity, IDA x16), GO:0071568, GO:0071569, ER membrane; downstream DNA-damage/immune/ERphagy roles KEEP_AS_NON_CORE. No contradictions.
  • PN story / NEW pressure: All PN assertions captured. GO:0006515 (verified) projected new_to_goa via RQC group is broad; UFL1's RQC role = ufmylation-driven 60S recycling (GO:0071569 annotated; review core_function explicitly describes RPL26β†’recycling). Conclusion: already captured; GO:0006515 over-reaches as a direct UFL1 term. (Note: the more specific GO:0072344 rescue-of-stalled-ribosome appears 4x in UFL1 GOA, a better fit than GO:0006515 if any RQC process were to be added.)
  • Mapping strategy: PN node correctly leaves the E3 UBL-modifier type at no_mapping and the E3 class at context-only GO:0061630 (ubiquitin protein ligase activity) β€” appropriately broad, not propagated. The gene-level specific MF is GO:0061666 (review). UFL1 does not change the node.
  • Evidence alignment: PN E3 row cites PMID:20018847 (shared β€” review uses it 7x, in GOA as IDA for GO:0061666), plus 25852645 and 20368332 (not in review; family/review citations). Good core-evidence overlap on the E3-ligase identification paper.
  • Verdict: Consistent and complete; PN E3/UFMylation/ERphagy story fully captured by GO:0061666 + GO:0071569. GO:0006515 broader than UFL1's already-annotated GO:0072344/GO:0071569 β€” not warranted as a direct add.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/UFL1/UFL1-ai-review.yaml
  • PN workbook rows: 3

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

  • UniProt: O94874
  • 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: O94874
  • In branches: TR, ALP, UPS
  • Notes: E3-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 | E3 ubiquitin and UBL ligases | UBL modifiers | UFMylation

  • UniProt: O94874
  • In branches: TR, ALP, UPS
  • Signature domains: IPR056579
  • Auxiliary domains: (none)
  • PN references (titles):
    • 25852645
    • 20018847
    • 20368332
  • PN-node mapping records (path + ancestors):
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|UBL modifiers|UFMylation
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a UBL-modifier subtype or architecture bucket. The subtree mixes catalytic ligases with cofactors/idiosyncratic contexts, so no direct GO propagation is made from this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|UBL modifiers
      status=context_only scope=too_broad_to_propagate GO=[GO:0019787 ubiquitin-like protein transferase activity]
      rationale: This group records UBL-modifier ligase context, but descendants include cofactors and idiosyncratic SUMOylation/ATGylation entries that are not uniformly transferase activities. Keep as context only.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [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 (4)

  • 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

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