UFSP2

UniProt ID: Q9NUQ7
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

UFSP2 (UFM1-specific protease 2) is the principal human UFM1-specific cysteine (thiol-dependent) isopeptidase of the peptidase C78 family (catalytic Cys302). It acts in the UFM1 (ubiquitin-fold modifier 1) conjugation system, where it both processes pro-UFM1 to expose the activating C-terminal glycine and, predominantly, removes UFM1 from conjugated target proteins (deUFMylation). Documented substrates include the ribosomal protein RPL26/uL24, CYB5R3, DDRGK1, MRE11, TRIP4 and CD274/PD-L1. At the cytoplasmic surface of the endoplasmic reticulum, UFSP2 deUFMylates RPL26 on 60S ribosomal subunits, a step required to release the UFM1 E3 ligase complex and recycle 60S subunits after ribosome-associated quality control of stalled ER-translocating ribosomes. Through deUFMylation of CYB5R3 it modulates ER-phagy, and through TRIP4 it influences nuclear-receptor (estrogen receptor) transactivation. Loss-of-function and missense UFSP2 variants cause autosomal-dominant skeletal dysplasias (Beukes hip dysplasia, spondyloepimetaphyseal dysplasia) and a recessive neurodevelopmental/epileptic encephalopathy.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005783 endoplasmic reticulum
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference that UFSP2 acts at the endoplasmic reticulum, where it deUFMylates RPL26 on ER-associated 60S ribosomes. Consistent with direct experimental evidence.
Reason: UFSP2 is an ER-membrane-tethered deUFMylase; the IBA localization is corroborated by direct IDA evidence.
Supporting Evidence:
PMID:38383785
ER-membrane-tethered deUFMylase UFSP2
GO:0071567 deUFMylase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference of UFM1-specific protease (deUFMylase) activity, the core molecular function of UFSP2, directly supported by extensive biochemistry.
Reason: deUFMylase activity is the central, repeatedly demonstrated function of UFSP2.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0005634 nucleus
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference of nuclear localization. Nuclear localization for human UFSP2 is supported only by sequence similarity to the mouse ortholog, not by direct human data; the dominant functional pool is at the ER/cytosol.
Reason: Possible minor nuclear pool (e.g. TRIP4-related nuclear-receptor regulation) but not the core site of UFSP2's deUFMylase function; retained as non-core.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Nucleus {ECO:0000250|UniProtKB:Q99K23}
GO:0006508 proteolysis
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Generic proteolysis term reflecting the peptidase activity of UFSP2. The specific activity is UFM1-specific isopeptide/peptide cleavage, better captured by deUFMylase activity and protein maturation.
Reason: Technically correct (UFSP2 is a protease) but uninformative compared with the specific deUFMylase activity; retained as non-core parent process.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0005634 nucleus
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic localization to nucleus, inherited from the mouse ortholog; see the IBA/ISS nucleus annotations.
Reason: Not the core site of action; supported only by orthology, retained as non-core.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Nucleus {ECO:0000250|UniProtKB:Q99K23}
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic localization to cytoplasm, consistent with the cytoplasmic/ER-surface site where UFSP2 acts on ribosomal and other substrates.
Reason: Cytoplasm (including the cytoplasmic face of the ER) is a documented compartment for UFSP2 activity.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Cytoplasm {ECO:0000250|UniProtKB:Q99K23}
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic localization to ER, consistent with the experimentally established ER-membrane-tethered localization of UFSP2.
Reason: ER is the principal functional site of UFSP2 (RPL26 deUFMylation); agrees with direct evidence.
Supporting Evidence:
PMID:38383785
ER-membrane-tethered deUFMylase UFSP2
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: High-throughput binary interactome screen recording UFSP2 interactions with APOBEC1 and LMO1; the bare protein binding term is uninformative and these partners do not inform UFSP2's deUFMylase function.
Reason: Records real interactions but the generic term is uninformative per curation guidelines; partners are not part of the core function.
Supporting Evidence:
file:human/UFSP2/UFSP2-goa.tsv
GO:0005515
GO:0032649 regulation of type II interferon production
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Ortholog-based (Ensembl) electronic annotation transferring an interferon-gamma production phenotype from the mouse gene. No direct human evidence; not part of the characterized UFM1-protease function.
Reason: Phenotype-based orthology transfer with no mechanistic link to UFSP2's deUFMylase activity in human; likely an indirect downstream consequence rather than a core function.
Supporting Evidence:
file:human/UFSP2/UFSP2-goa.tsv
GO:0032649
GO:0071567 deUFMylase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated electronic annotation of deUFMylase activity, redundant with and consistent with extensive experimental support.
Reason: Correct core molecular function.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0005634 nucleus
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence-similarity-based nuclear localization transferred from the mouse ortholog (Q99K23). See the IBA/IEA nucleus annotations.
Reason: Orthology-only support; not the core functional compartment.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Nucleus {ECO:0000250|UniProtKB:Q99K23}
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity-based cytoplasmic localization, consistent with the cytoplasmic/ER-surface site of UFSP2 action.
Reason: Cytoplasmic localization is well supported, including by direct human data.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Cytoplasm {ECO:0000250|UniProtKB:Q99K23}
GO:0071567 deUFMylase activity
IDA
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostas... 		ACCEPT
Summary: Direct evidence for UFSP2 deUFMylase activity in the context of HRD1 UFMylation and ER homeostasis.
Reason: Direct experimental support for the core deUFMylase activity.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0071567 deUFMylase activity
IDA
PMID:36893266
Dysregulation of PD-L1 by UFMylation imparts tumor immune ev... 		ACCEPT
Summary: Direct evidence for UFSP2 deUFMylase activity.
Reason: Direct experimental support for the core deUFMylase activity.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0042177 negative regulation of protein catabolic process
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		KEEP AS NON CORE
Summary: UFSP2 deUFMylates CYB5R3; because CYB5R3 UFMylation signals ER-phagy (degradation), UFSP2 activity opposes this catabolic route. The negative regulation of a degradation process is a downstream consequence of its deUFMylase activity.
Reason: Plausible process outcome of UFSP2 reversing CYB5R3 UFMylation, but a downstream/context-specific effect rather than the core molecular function.
Supporting Evidence:
PMID:36543799
overexpression of UFSP2 but not the active-site mutant UFSP2C302A decreased the amount of the UFM1~CYB5R3 conjugate
GO:0071567 deUFMylase activity
IDA
PMID:31595041
UFMylation of RPL26 links translocation-associated quality c... 		ACCEPT
Summary: Direct evidence for UFSP2 deUFMylase activity on a target substrate.
Reason: Direct experimental support for the core deUFMylase activity.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0071567 deUFMylase activity
IDA
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of... 		ACCEPT
Summary: Direct demonstration that wild-type UFSP2, but not the catalytic Cys302Ala mutant, removes UFM1 from CYB5R3, establishing UFSP2 deUFMylase activity on this ER substrate.
Reason: Active-site-dependent removal of UFM1 from a defined substrate; strong direct support for the core function.
Supporting Evidence:
PMID:36543799
overexpression of UFSP2 but not the active-site mutant UFSP2C302A decreased the amount of the UFM1~CYB5R3 conjugate
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: UFSP2 deUFMylation of RPL26/uL24 is required to release the UFM1 E3 ligase from UFMylated 60S subunits, enabling 60S recycling after RQC-mediated splitting of ribosomes stalled during co-translational ER translocation.
Reason: Directly supported role in the ribosome-rescue/recycling arm of ER-associated RQC; this is a key biological process for UFSP2.
Supporting Evidence:
PMID:38383785
UFMylation facilitates the rescue of 60S ribosomal subunits (60S) that are released after ribosome-associated quality-control-mediated splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER
GO:0005783 endoplasmic reticulum
IDA
PMID:35926457
Human UFSP1 is an active protease that regulates UFM1 matura... 		ACCEPT
Summary: Direct evidence that UFSP2 acts at the ER (in contrast to cytosolic UFSP1), where it removes UFM1 from the ribosomal subunit RPL26.
Reason: Establishes the ER as the functional compartment for UFSP2's RPL26 deUFMylation.
Supporting Evidence:
PMID:35926457
While UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26
GO:0032790 ribosome disassembly
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: UFSP2-mediated deUFMylation of RPL26 releases the UFM1 E3 ligase clamp from the 60S subunit, contributing to disassembly/recycling of post-RQC 60S ribosomal subunits.
Reason: Directly supported role in releasing the E3-UFM1 clamp to allow 60S recycling.
Supporting Evidence:
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER
GO:0071567 deUFMylase activity
IMP
PMID:27926783
A novel approach to assess the ubiquitin-fold modifier 1-sys... 		ACCEPT
Summary: Mutational/phenotypic evidence supporting UFSP2 as the active deUFMylase mediating deconjugation of UFM1 from target proteins.
Reason: Supports the core deUFMylase activity; UFSP2 mainly acts as a protein deUFMylase.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
UFSP2 mainly acts as a protein deUFMylase that mediates deconjugation of UFM1 from target proteins
GO:0071567 deUFMylase activity
IDA
PMID:35926457
Human UFSP1 is an active protease that regulates UFM1 matura... 		ACCEPT
Summary: Direct evidence that UFSP2 removes UFM1 from RPL26, confirming deUFMylase activity.
Reason: Direct experimental support for the core deUFMylase activity.
Supporting Evidence:
PMID:35926457
While UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26
GO:0071567 deUFMylase activity
IDA
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits ... 		ACCEPT
Summary: UFSP2 deUFMylates RPL26 on 60S subunits, the activity underlying 60S recycling.
Reason: Direct support for the core deUFMylase activity in the ribosome-recycling context.
Supporting Evidence:
PMID:38383785
ER-membrane-tethered deUFMylase UFSP2
GO:0071567 deUFMylase activity
IMP
PMID:33473208
A pathogenic UFSP2 variant in an autosomal recessive form of... 		ACCEPT
Summary: A pathogenic UFSP2 variant impairs UFMylation homeostasis, consistent with UFSP2 functioning as the active UFM1-specific peptidase; mutant phenotype supports the enzymatic role.
Reason: Disease-variant evidence supports UFSP2's deUFMylase/UFM1-protease function.
Supporting Evidence:
PMID:33473208
UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway
GO:0071567 deUFMylase activity
IMP
PMID:32160526
A Genome-wide ER-phagy Screen Highlights Key Roles of Mitoch... 		ACCEPT
Summary: Mutational evidence supporting UFSP2 deUFMylase activity.
Reason: Supports the core deUFMylase activity.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0033146 regulation of intracellular estrogen receptor signaling pathway
IMP
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: UFSP2 deUFMylates the coactivator TRIP4/ASC-1, regulating nuclear-receptor (including estrogen receptor) transactivation. A context-specific downstream role of UFSP2's deUFMylase activity.
Reason: A genuine but context-specific regulatory process downstream of UFSP2 deUFMylating TRIP4; not the core molecular function.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Catalyzes deUFMylation of TRIP4, regulating intracellular nuclear receptors transactivation
GO:0006508 proteolysis
IMP
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: Generic proteolysis term reflecting UFSP2's peptidase activity (here in the TRIP4 deUFMylation study). The specific activity is UFM1-specific cleavage.
Reason: Correct but uninformative parent term relative to deUFMylase activity.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Thiol-dependent isopeptidase that specifically cleaves UFM1
GO:0071567 deUFMylase activity
IMP
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		ACCEPT
Summary: UFSP2 deUFMylates TRIP4; mutational/functional evidence supports the deUFMylase activity on this substrate.
Reason: Supports the core deUFMylase activity with a defined substrate (TRIP4).
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Catalyzes deUFMylation of TRIP4, regulating intracellular nuclear receptors transactivation
GO:0005515 protein binding
IPI
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivat... 		KEEP AS NON CORE
Summary: Records a UFSP2-TRIP4 (Q15650) interaction (the substrate it deUFMylates). The bare protein binding term is uninformative; the functionally meaningful relationship is enzyme-substrate.
Reason: Reflects the UFSP2-TRIP4 substrate interaction but the generic term is uninformative per curation guidelines.
Supporting Evidence:
file:human/UFSP2/UFSP2-uniprot.txt
Catalyzes deUFMylation of TRIP4, regulating intracellular nuclear receptors transactivation

Core Functions

UFM1-specific cysteine (thiol-dependent) protease that removes UFM1 from conjugated substrates (deUFMylation), most prominently RPL26/uL24 on ER-associated 60S ribosomal subunits, and also processes pro-UFM1; catalytic residue Cys302.

Molecular Function:
deUFMylase activity
Cellular Locations:
endoplasmic reticulum
Supporting Evidence:
  • file:human/UFSP2/UFSP2-uniprot.txt
    UFSP2 mainly acts as a protein deUFMylase that mediates deconjugation of UFM1 from target proteins
  • PMID:35926457
    While UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26

deUFMylation of RPL26/uL24 releases the UFM1 E3 ligase from UFMylated 60S subunits, enabling recycling of 60S ribosomal subunits after ribosome-associated quality control of ribosomes that stall during co-translational ER translocation.

Molecular Function:
deUFMylase activity
Cellular Locations:
endoplasmic reticulum
Supporting Evidence:
  • PMID:38383785
    UFMylation facilitates the rescue of 60S ribosomal subunits (60S) that are released after ribosome-associated quality-control-mediated splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER
  • PMID:38383785
    ER-membrane-tethered deUFMylase UFSP2

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:25219498
Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
  • UFSP2 deUFMylates the coactivator TRIP4, regulating nuclear-receptor (including estrogen receptor) transactivation.
PMID:27926783
A novel approach to assess the ubiquitin-fold modifier 1-system in cells.
  • UFSP2 mainly acts as a protein deUFMylase deconjugating UFM1 from target proteins.
PMID:31595041
UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis.
PMID:32160526
A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33473208
A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.
  • A homozygous UFSP2 variant in the UFM1-specific peptidase 2 causes a recessive pediatric neurodevelopmental disorder with epilepsy, affecting UFMylation.
PMID:35926457
Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation.
  • UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26; UFSP2 acts at the ER.
PMID:36543799
The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
  • Wild-type UFSP2, but not the active-site mutant UFSP2C302A, removes UFM1 from CYB5R3; CYB5R3 UFMylation signals ER-phagy required for neuronal development.
PMID:36893266
Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target.
PMID:37795761
UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
  • UFSP2 deUFMylase activity acts in the context of HRD1 UFMylation and ER homeostasis.
PMID:38383785
UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.
  • UFM1 modifies RPL26/uL24 on ER ribosomes to facilitate rescue/recycling of 60S subunits after RQC splitting; UFSP2 is the ER-membrane-tethered deUFMylase that removes this mark.

Suggested Questions for Experts

Q: How is the choice between UFSP2 pro-UFM1 maturation and substrate deUFMylation regulated, and what determines its substrate selectivity (RPL26 vs CYB5R3 vs TRIP4)?

Q: How do the skeletal-dysplasia missense variants versus the recessive neurodevelopmental variant differ mechanistically in their effect on UFSP2 catalysis and the resulting UFMylation balance?

Suggested Experiments

Experiment: Substrate-resolved UFM1-conjugate proteomics in UFSP2-knockout versus catalytically dead (C302A) rescue cells to map the in vivo deUFMylation substrate repertoire.

Experiment: Reconstitute UFMylated 60S recycling in vitro with purified UFSP2 to test whether RPL26 deUFMylation is necessary and sufficient to release the UFM1 E3 ligase clamp.

πŸ“š Additional Documentation

Notes

(UFSP2-notes.md)

UFSP2 (Q9NUQ7) research notes

Summary

UFSP2 (UFM1-specific protease 2) is the principal human UFM1-specific cysteine (thiol-dependent) isopeptidase of the peptidase C78 family (catalytic Cys302). It acts in the UFM1 (ubiquitin-fold modifier 1) conjugation system, where it both processes pro-UFM1 to expose the activating C-terminal glycine and, predominantly, removes UFM1 from conjugated target proteins (deUFMylation). Documented substrates include the ribosomal protein RPL26/uL24, CYB5R3, DDRGK1, MRE11, TRIP4 and CD274/PD-L1. At the cytoplasmic surface of the endoplasmic reticulum, UFSP2 deUFMylates RPL26 on 60S ribosomal subunits, a step required to release the UFM1 E3 ligase complex and recycle 60S subunits after ribosome-associated quality control of stalled ER-translocating ribosomes. Through deUFMylation of CYB5R3 it modulates ER-phagy, and through TRIP4 it influences nuclear-receptor (estrogen receptor) transactivation. Loss-of-function and missense UFSP2 variants cause autosomal-dominant skeletal dysplasias (Beukes hip dysplasia, spondyloepimetaphyseal dysplasia) and a recessive neurodevelopmental/epileptic encephalopathy.

Core functions (from review)

  • GO:0071567 deUFMylase activity β€” UFM1-specific cysteine (thiol-dependent) protease that removes UFM1 from conjugated substrates (deUFMylation), most prominently RPL26/uL24 on ER-associated 60S ribosomal subunits, and also processes pro-UFM1; catalytic residue Cys302.
  • GO:0071567 deUFMylase activity β€” deUFMylation of RPL26/uL24 releases the UFM1 E3 ligase from UFMylated 60S subunits, enabling recycling of 60S ribosomal subunits after ribosome-associated quality control of ribosomes that stall during co-translational ER translocation.

Provenance

Research and verbatim supporting quotes are recorded inline in UFSP2-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(UFSP2-pn-notes.md)

UFSP2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9NUQ7
  • 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: UFSP2 (UFM1-specific protease 2) is the principal human UFM1-specific cysteine (thiol-dependent) isopeptidase of the peptidase C78 family (catalytic Cys302). It acts in the UFM1 (ubiquitin-fold modifier 1) conjugation system, where it both processes pro-UFM1 to expose the activating C-terminal glycine and, predominantly, removes UFM1 from conjugated target proteins (deUFMylation). Documented substrates include the ribosomal protein RPL26/uL24, CYB5R3, DDRGK1, MRE11, TRIP4 and CD274/PD-L1. At the cytoplasmic surface of the endoplasmic reticulum, UFSP2 deUFMylates RPL26 on 60S ribosomal subunits, a step required to release the UFM1 E3 ligase complex and recycle 60S subunits after ribosome-associated quality control of stalled ER-translocating ribosomes. Through deUFMylation of CYB5R3 it modulates ER-phagy, and through TRIP4 it influences nuclear-receptor (estrogen receptor) transactivation. Loss-of-function and missense UFSP2 variants cause autosomal-dominant skeletal dysplasias (Beukes hip dysplasia, spondyloepimetaphyseal dysplasia) and a recessive neurodevelopmental/epileptic encephalopathy.
  • Existing/core annotation action counts: ACCEPT: 19; KEEP_AS_NON_CORE: 9; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Strong. Deep-research/notes, review YAML, PN annotation and PN-node mapping agree: UFSP2 is the principal human UFM1-specific cysteine protease (Cys302) that deUFMylates substrates (RPL26/uL24, CYB5R3, TRIP4, etc.) and processes pro-UFM1; ER-membrane-tethered, acting on 60S after RQC splitting. GOA cross-check confirms goa_status: GO:0071567 already-in-GOA (12 records), GO:0071569 new-to-GOA (0), GO:0006515 new-to-GOA (0). No contradictions.
  • PN story / NEW pressure: PN's deUFMylase/ufmylation story is captured (GO:0071567 multiple IDA/IMP/IBA). The RQC-specific biology is ALSO captured by review-only terms NOT generated from the PN node: GO:0072344 rescue of stalled cytosolic ribosome (IDA, PMID:38383785) and GO:0032790 ribosome disassembly (IDA) β€” these are more precise than the PN group's GO:0006515 and are already in the review. So GO:0006515 (new-to-GOA) is defensible-but-redundant for UFSP2; the better RQC terms already exist. No new term required.
  • Evidence alignment: PN row 2 cites PMID:29476094 (UFSP review) β€” absent from the review YAML, which spans many primaries (PMID:38383785, 35926457, 36543799, 25219498, 31595041, 27926783, 33473208, 32160526, 36893266, 37795761). Same biology; PN reference is a secondary review not used in the YAML.
  • Verdict: Consistent and complete; PN-projected GO:0006515 is correct but broader than the review's already-present GO:0072344/GO:0032790.

Full Consistency Review

  • UniProt: Q9NUQ7 Β· batch: proteostasis-batch-2026-06-07c Β· review status: COMPLETE
  • PN placement: two rows β€” Translation|Cytosolic translation|Ribosome-associated QC|UFMylation and Ubiquitin Proteasome System|DUBs and UBL demodifiers|UFSP|deUFMylase ; PN-node mapping: type/group both mapped, ok_for_propagation β†’ GO:0071569 protein ufmylation, GO:0071567 deUFMylase activity, group-level GO:0006515 PQC (from RQC group); UPS class/branch no_mapping.
  • Consistency: Strong. Deep-research/notes, review YAML, PN annotation and PN-node mapping agree: UFSP2 is the principal human UFM1-specific cysteine protease (Cys302) that deUFMylates substrates (RPL26/uL24, CYB5R3, TRIP4, etc.) and processes pro-UFM1; ER-membrane-tethered, acting on 60S after RQC splitting. GOA cross-check confirms goa_status: GO:0071567 already-in-GOA (12 records), GO:0071569 new-to-GOA (0), GO:0006515 new-to-GOA (0). No contradictions.
  • PN story / NEW pressure: PN's deUFMylase/ufmylation story is captured (GO:0071567 multiple IDA/IMP/IBA). The RQC-specific biology is ALSO captured by review-only terms NOT generated from the PN node: GO:0072344 rescue of stalled cytosolic ribosome (IDA, PMID:38383785) and GO:0032790 ribosome disassembly (IDA) β€” these are more precise than the PN group's GO:0006515 and are already in the review. So GO:0006515 (new-to-GOA) is defensible-but-redundant for UFSP2; the better RQC terms already exist. No new term required.
  • Mapping strategy: Unlike UFSP1, the GROUPβ†’GO:0006515/RQC projection IS biologically defensible for UFSP2 (RPL26 deUFMylation enabling 60S recycling after RQC). However the review already holds the narrower, IDA-backed GO:0072344 / GO:0032790; GO:0006515 is broader than these. UPS-side deUFMylase node anchoring is correct.
  • Evidence alignment: PN row 2 cites PMID:29476094 (UFSP review) β€” absent from the review YAML, which spans many primaries (PMID:38383785, 35926457, 36543799, 25219498, 31595041, 27926783, 33473208, 32160526, 36893266, 37795761). Same biology; PN reference is a secondary review not used in the YAML.
  • Verdict: Consistent and complete; PN-projected GO:0006515 is correct but broader than the review's already-present GO:0072344/GO:0032790.

Recommended edits: [MAP] the RQC-group GO:0006515 projection is acceptable for UFSP2 but redundant/broader than the review's existing GO:0072344 (rescue of stalled cytosolic ribosome) and GO:0032790 (ribosome disassembly); prefer those narrower IDA-supported terms when representing UFSP2's RQC role.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/UFSP2/UFSP2-ai-review.yaml
  • PN workbook rows: 2

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

  • UniProt: Q9NUQ7
  • In branches: TR, 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: Ubiquitin Proteasome System | DUBs and UBL demodifiers | UFSP | deUFMylase

  • UniProt: Q9NUQ7
  • In branches: TR, UPS
  • Signature domains: IPR012462
  • Auxiliary domains: (none)
  • PN references (titles):
    • 29476094
  • PN-node mapping records (path + ancestors):
    • [type] Ubiquitin Proteasome System|DUBs and UBL demodifiers|UFSP|deUFMylase
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0071567 deUFMylase activity]
      rationale: This PN type is the explicit deUFMylase bucket under UFSP proteins. The matching GO molecular-function term is deUFMylase activity.
    • [group] Ubiquitin Proteasome System|DUBs and UBL demodifiers|UFSP
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0071567 deUFMylase activity]
      rationale: This PN group captures UFSP-family deUFMylases. The matching GO molecular-function term is deUFMylase activity.
    • [class] Ubiquitin Proteasome System|DUBs and UBL demodifiers
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
    • [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=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC|UFMylation
  • GO:0071567 deUFMylase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|DUBs and UBL demodifiers|UFSP
  • GO:0071567 deUFMylase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|DUBs and UBL demodifiers|UFSP|deUFMylase

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: Q9NUQ7
gene_symbol: UFSP2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UFSP2 (UFM1-specific protease 2) is the principal human UFM1-specific cysteine
  (thiol-dependent) isopeptidase of the peptidase C78 family (catalytic Cys302). It
  acts in the UFM1 (ubiquitin-fold modifier 1) conjugation system, where it both processes
  pro-UFM1 to expose the activating C-terminal glycine and, predominantly, removes
  UFM1 from conjugated target proteins (deUFMylation). Documented substrates include
  the ribosomal protein RPL26/uL24, CYB5R3, DDRGK1, MRE11, TRIP4 and CD274/PD-L1.
  At the cytoplasmic surface of the endoplasmic reticulum, UFSP2 deUFMylates RPL26
  on 60S ribosomal subunits, a step required to release the UFM1 E3 ligase complex
  and recycle 60S subunits after ribosome-associated quality control of stalled ER-translocating
  ribosomes. Through deUFMylation of CYB5R3 it modulates ER-phagy, and through TRIP4
  it influences nuclear-receptor (estrogen receptor) transactivation. Loss-of-function
  and missense UFSP2 variants cause autosomal-dominant skeletal dysplasias (Beukes
  hip dysplasia, spondyloepimetaphyseal dysplasia) and a recessive neurodevelopmental/epileptic
  encephalopathy.
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference that UFSP2 acts at the endoplasmic reticulum, where it deUFMylates RPL26 on ER-associated 60S ribosomes. Consistent with direct experimental evidence.
    action: ACCEPT
    reason: UFSP2 is an ER-membrane-tethered deUFMylase; the IBA localization is corroborated by direct IDA evidence.
    supported_by:
    - reference_id: PMID:38383785
      supporting_text: ER-membrane-tethered deUFMylase UFSP2
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of UFM1-specific protease (deUFMylase) activity, the core molecular function of UFSP2, directly supported by extensive biochemistry.
    action: ACCEPT
    reason: deUFMylase activity is the central, repeatedly demonstrated function of UFSP2.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of nuclear localization. Nuclear localization for human UFSP2 is supported only by sequence similarity to the mouse ortholog, not by direct human data; the dominant functional pool is at the ER/cytosol.
    action: KEEP_AS_NON_CORE
    reason: Possible minor nuclear pool (e.g. TRIP4-related nuclear-receptor regulation) but not the core site of UFSP2's deUFMylase function; retained as non-core.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Nucleus {ECO:0000250|UniProtKB:Q99K23}
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Generic proteolysis term reflecting the peptidase activity of UFSP2. The specific activity is UFM1-specific isopeptide/peptide cleavage, better captured by deUFMylase activity and protein maturation.
    action: KEEP_AS_NON_CORE
    reason: Technically correct (UFSP2 is a protease) but uninformative compared with the specific deUFMylase activity; retained as non-core parent process.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic localization to nucleus, inherited from the mouse ortholog; see the IBA/ISS nucleus annotations.
    action: KEEP_AS_NON_CORE
    reason: Not the core site of action; supported only by orthology, retained as non-core.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Nucleus {ECO:0000250|UniProtKB:Q99K23}
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic localization to cytoplasm, consistent with the cytoplasmic/ER-surface site where UFSP2 acts on ribosomal and other substrates.
    action: ACCEPT
    reason: Cytoplasm (including the cytoplasmic face of the ER) is a documented compartment for UFSP2 activity.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000250|UniProtKB:Q99K23}
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic localization to ER, consistent with the experimentally established ER-membrane-tethered localization of UFSP2.
    action: ACCEPT
    reason: ER is the principal functional site of UFSP2 (RPL26 deUFMylation); agrees with direct evidence.
    supported_by:
    - reference_id: PMID:38383785
      supporting_text: ER-membrane-tethered deUFMylase UFSP2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome screen recording UFSP2 interactions with APOBEC1 and LMO1; the bare protein binding term is uninformative and these partners do not inform UFSP2's deUFMylase function.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions but the generic term is uninformative per curation guidelines; partners are not part of the core function.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-goa.tsv
      supporting_text: GO:0005515
- term:
    id: GO:0032649
    label: regulation of type II interferon production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based (Ensembl) electronic annotation transferring an interferon-gamma production phenotype from the mouse gene. No direct human evidence; not part of the characterized UFM1-protease function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Phenotype-based orthology transfer with no mechanistic link to UFSP2's deUFMylase activity in human; likely an indirect downstream consequence rather than a core function.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-goa.tsv
      supporting_text: GO:0032649
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated electronic annotation of deUFMylase activity, redundant with and consistent with extensive experimental support.
    action: ACCEPT
    reason: Correct core molecular function.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based nuclear localization transferred from the mouse ortholog (Q99K23). See the IBA/IEA nucleus annotations.
    action: KEEP_AS_NON_CORE
    reason: Orthology-only support; not the core functional compartment.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Nucleus {ECO:0000250|UniProtKB:Q99K23}
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based cytoplasmic localization, consistent with the cytoplasmic/ER-surface site of UFSP2 action.
    action: ACCEPT
    reason: Cytoplasmic localization is well supported, including by direct human data.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000250|UniProtKB:Q99K23}
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:37795761
  qualifier: enables
  review:
    summary: Direct evidence for UFSP2 deUFMylase activity in the context of HRD1 UFMylation and ER homeostasis.
    action: ACCEPT
    reason: Direct experimental support for the core deUFMylase activity.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:36893266
  qualifier: enables
  review:
    summary: Direct evidence for UFSP2 deUFMylase activity.
    action: ACCEPT
    reason: Direct experimental support for the core deUFMylase activity.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0042177
    label: negative regulation of protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: involved_in
  review:
    summary: UFSP2 deUFMylates CYB5R3; because CYB5R3 UFMylation signals ER-phagy (degradation), UFSP2 activity opposes this catabolic route. The negative regulation of a degradation process is a downstream consequence of its deUFMylase activity.
    action: KEEP_AS_NON_CORE
    reason: Plausible process outcome of UFSP2 reversing CYB5R3 UFMylation, but a downstream/context-specific effect rather than the core molecular function.
    supported_by:
    - reference_id: PMID:36543799
      supporting_text: overexpression of UFSP2 but not the active-site mutant UFSP2C302A decreased the amount of the UFM1~CYB5R3 conjugate
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:31595041
  qualifier: enables
  review:
    summary: Direct evidence for UFSP2 deUFMylase activity on a target substrate.
    action: ACCEPT
    reason: Direct experimental support for the core deUFMylase activity.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:36543799
  qualifier: enables
  review:
    summary: Direct demonstration that wild-type UFSP2, but not the catalytic Cys302Ala mutant, removes UFM1 from CYB5R3, establishing UFSP2 deUFMylase activity on this ER substrate.
    action: ACCEPT
    reason: Active-site-dependent removal of UFM1 from a defined substrate; strong direct support for the core function.
    supported_by:
    - reference_id: PMID:36543799
      supporting_text: overexpression of UFSP2 but not the active-site mutant UFSP2C302A decreased the amount of the UFM1~CYB5R3 conjugate
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: UFSP2 deUFMylation of RPL26/uL24 is required to release the UFM1 E3 ligase from UFMylated 60S subunits, enabling 60S recycling after RQC-mediated splitting of ribosomes stalled during co-translational ER translocation.
    action: ACCEPT
    reason: Directly supported role in the ribosome-rescue/recycling arm of ER-associated RQC; this is a key biological process for UFSP2.
    supported_by:
    - reference_id: PMID:38383785
      supporting_text: UFMylation facilitates the rescue of 60S ribosomal subunits (60S) that are released after ribosome-associated quality-control-mediated splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:35926457
  qualifier: is_active_in
  review:
    summary: Direct evidence that UFSP2 acts at the ER (in contrast to cytosolic UFSP1), where it removes UFM1 from the ribosomal subunit RPL26.
    action: ACCEPT
    reason: Establishes the ER as the functional compartment for UFSP2's RPL26 deUFMylation.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: While UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26
- term:
    id: GO:0032790
    label: ribosome disassembly
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: involved_in
  review:
    summary: UFSP2-mediated deUFMylation of RPL26 releases the UFM1 E3 ligase clamp from the 60S subunit, contributing to disassembly/recycling of post-RQC 60S ribosomal subunits.
    action: ACCEPT
    reason: Directly supported role in releasing the E3-UFM1 clamp to allow 60S recycling.
    supported_by:
    - reference_id: PMID:38383785
      supporting_text: UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IMP
  original_reference_id: PMID:27926783
  qualifier: enables
  review:
    summary: Mutational/phenotypic evidence supporting UFSP2 as the active deUFMylase mediating deconjugation of UFM1 from target proteins.
    action: ACCEPT
    reason: Supports the core deUFMylase activity; UFSP2 mainly acts as a protein deUFMylase.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: UFSP2 mainly acts as a protein deUFMylase that mediates deconjugation of UFM1 from target proteins
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:35926457
  qualifier: enables
  review:
    summary: Direct evidence that UFSP2 removes UFM1 from RPL26, confirming deUFMylase activity.
    action: ACCEPT
    reason: Direct experimental support for the core deUFMylase activity.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: While UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:38383785
  qualifier: enables
  review:
    summary: UFSP2 deUFMylates RPL26 on 60S subunits, the activity underlying 60S recycling.
    action: ACCEPT
    reason: Direct support for the core deUFMylase activity in the ribosome-recycling context.
    supported_by:
    - reference_id: PMID:38383785
      supporting_text: ER-membrane-tethered deUFMylase UFSP2
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IMP
  original_reference_id: PMID:33473208
  qualifier: enables
  review:
    summary: A pathogenic UFSP2 variant impairs UFMylation homeostasis, consistent with UFSP2 functioning as the active UFM1-specific peptidase; mutant phenotype supports the enzymatic role.
    action: ACCEPT
    reason: Disease-variant evidence supports UFSP2's deUFMylase/UFM1-protease function.
    supported_by:
    - reference_id: PMID:33473208
      supporting_text: UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IMP
  original_reference_id: PMID:32160526
  qualifier: enables
  review:
    summary: Mutational evidence supporting UFSP2 deUFMylase activity.
    action: ACCEPT
    reason: Supports the core deUFMylase activity.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0033146
    label: regulation of intracellular estrogen receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: UFSP2 deUFMylates the coactivator TRIP4/ASC-1, regulating nuclear-receptor (including estrogen receptor) transactivation. A context-specific downstream role of UFSP2's deUFMylase activity.
    action: KEEP_AS_NON_CORE
    reason: A genuine but context-specific regulatory process downstream of UFSP2 deUFMylating TRIP4; not the core molecular function.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Catalyzes deUFMylation of TRIP4, regulating intracellular nuclear receptors transactivation
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IMP
  original_reference_id: PMID:25219498
  qualifier: involved_in
  review:
    summary: Generic proteolysis term reflecting UFSP2's peptidase activity (here in the TRIP4 deUFMylation study). The specific activity is UFM1-specific cleavage.
    action: KEEP_AS_NON_CORE
    reason: Correct but uninformative parent term relative to deUFMylase activity.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Thiol-dependent isopeptidase that specifically cleaves UFM1
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IMP
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: UFSP2 deUFMylates TRIP4; mutational/functional evidence supports the deUFMylase activity on this substrate.
    action: ACCEPT
    reason: Supports the core deUFMylase activity with a defined substrate (TRIP4).
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Catalyzes deUFMylation of TRIP4, regulating intracellular nuclear receptors transactivation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25219498
  qualifier: enables
  review:
    summary: Records a UFSP2-TRIP4 (Q15650) interaction (the substrate it deUFMylates). The bare protein binding term is uninformative; the functionally meaningful relationship is enzyme-substrate.
    action: KEEP_AS_NON_CORE
    reason: Reflects the UFSP2-TRIP4 substrate interaction but the generic term is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
      supporting_text: Catalyzes deUFMylation of TRIP4, regulating intracellular nuclear receptors transactivation
core_functions:
- description: UFM1-specific cysteine (thiol-dependent) protease that removes UFM1 from conjugated substrates (deUFMylation), most prominently RPL26/uL24 on ER-associated 60S ribosomal subunits, and also processes pro-UFM1; catalytic residue Cys302.
  molecular_function:
    id: GO:0071567
    label: deUFMylase activity
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: file:human/UFSP2/UFSP2-uniprot.txt
    supporting_text: UFSP2 mainly acts as a protein deUFMylase that mediates deconjugation of UFM1 from target proteins
  - reference_id: PMID:35926457
    supporting_text: While UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26
- description: deUFMylation of RPL26/uL24 releases the UFM1 E3 ligase from UFMylated 60S subunits, enabling recycling of 60S ribosomal subunits after ribosome-associated quality control of ribosomes that stall during co-translational ER translocation.
  molecular_function:
    id: GO:0071567
    label: deUFMylase activity
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: PMID:38383785
    supporting_text: UFMylation facilitates the rescue of 60S ribosomal subunits (60S) that are released after ribosome-associated quality-control-mediated splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER
  - reference_id: PMID:38383785
    supporting_text: ER-membrane-tethered deUFMylase UFSP2
proposed_new_terms: []
suggested_questions:
- question: How is the choice between UFSP2 pro-UFM1 maturation and substrate deUFMylation regulated, and what determines its substrate selectivity (RPL26 vs CYB5R3 vs TRIP4)?
- question: How do the skeletal-dysplasia missense variants versus the recessive neurodevelopmental variant differ mechanistically in their effect on UFSP2 catalysis and the resulting UFMylation balance?
suggested_experiments:
- description: Substrate-resolved UFM1-conjugate proteomics in UFSP2-knockout versus catalytically dead (C302A) rescue cells to map the in vivo deUFMylation substrate repertoire.
- description: Reconstitute UFMylated 60S recycling in vitro with purified UFSP2 to test whether RPL26 deUFMylation is necessary and sufficient to release the UFM1 E3 ligase clamp.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:25219498
  title: Modification of ASC1 by UFM1 is crucial for ERΞ± transactivation and breast cancer development.
  findings:
  - statement: UFSP2 deUFMylates the coactivator TRIP4, regulating nuclear-receptor (including estrogen receptor) transactivation.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Not cached; supporting facts taken from the UniProt FUNCTION summary citing this PMID.
- id: PMID:27926783
  title: 'A novel approach to assess the ubiquitin-fold modifier 1-system in cells.'
  findings:
  - statement: UFSP2 mainly acts as a protein deUFMylase deconjugating UFM1 from target proteins.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Not cached; supporting facts taken from the UniProt FUNCTION summary citing this PMID.
- id: PMID:31595041
  title: 'UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Not cached; cited by UniProt for UFSP2 deUFMylase activity.
- id: PMID:32160526
  title: A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Not cached; cited by UniProt for UFSP2 deUFMylase activity.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary interactome; partners (APOBEC1, LMO1) do not inform UFSP2 function.
- id: PMID:33473208
  title: A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.
  findings:
  - statement: A homozygous UFSP2 variant in the UFM1-specific peptidase 2 causes a recessive pediatric neurodevelopmental disorder with epilepsy, affecting UFMylation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; links UFSP2 enzymatic function to neurodevelopmental disease.
- id: PMID:35926457
  title: Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation.
  findings:
  - statement: UFSP2, but not UFSP1, removes UFM1 from the ribosomal subunit RPL26; UFSP2 acts at the ER.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; distinguishes UFSP2 (ER, RPL26) from UFSP1.
- id: PMID:36543799
  title: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
  findings:
  - statement: Wild-type UFSP2, but not the active-site mutant UFSP2C302A, removes UFM1 from CYB5R3; CYB5R3 UFMylation signals ER-phagy required for neuronal development.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; CYB5R3 deUFMylation by UFSP2 (Cys302-dependent).
- id: PMID:36893266
  title: Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Not cached; cited by UniProt/GOA for UFSP2 deUFMylase activity (IDA).
- id: PMID:37795761
  title: UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
  findings:
  - statement: UFSP2 deUFMylase activity acts in the context of HRD1 UFMylation and ER homeostasis.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified title; cited for UFSP2 deUFMylase activity (IDA).
- id: PMID:38383785
  title: UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.
  findings:
  - statement: UFM1 modifies RPL26/uL24 on ER ribosomes to facilitate rescue/recycling of 60S subunits after RQC splitting; UFSP2 is the ER-membrane-tethered deUFMylase that removes this mark.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; defines UFSP2's role in 60S recycling / ribosome disassembly.