Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0071567 deUFMylase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of UFM1-specific protease (deUFMylase) activity across the UFSP family. This is the core molecular function of UFSP1 and is directly supported by experimental evidence for the human protein. Reason: deUFMylase activity is the central, experimentally confirmed function of UFSP1; the IBA call is corroborated by direct biochemical assays. Supporting Evidence: PMID:35525273 both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic localization to cytosol, consistent with the experimentally determined cytosolic localization of UFSP1. Reason: Cytosol is the documented site of UFSP1 action; the IEA call agrees with direct subcellular fractionation evidence. Supporting Evidence: file:human/UFSP1/UFSP1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: High-throughput binary (Y2H) human interactome screen recording ~40 partners (largely transcription factors and unrelated proteins). The bare protein binding term is uninformative and the partners do not converge on a coherent UFSP1 function. Reason: Records real binary interactions but the generic term carries no functional information and the partners are not part of UFSP1's UFM1-protease function; retained as non-core per curation guidelines on protein binding. Supporting Evidence: file:human/UFSP1/UFSP1-goa.tsv GO:0005515
GO:0071567 deUFMylase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated electronic annotation of deUFMylase activity, redundant with and consistent with the experimentally supported IDA annotations. Reason: Correct core molecular function; agrees with stronger experimental evidence. Supporting Evidence: PMID:35926457 UFSP1 effectively cleaved UFM1 from these different substrates
GO:0071569 protein ufmylation	IDA PMID:35525273 Human UFSP1 translated from an upstream near-cognate initiat...	ACCEPT	Summary: UFSP1 is involved in protein UFMylation by maturing pro-UFM1, a prerequisite for conjugation, and by reversing UFM1 conjugation. This is the correct biological-process context for its protease activity. Reason: By generating mature UFM1 and removing an autoinhibitory UFM1 mark on UFC1, UFSP1 directly controls the activation of the UFMylation pathway. Supporting Evidence: PMID:35525273 both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins
GO:0071569 protein ufmylation	IDA PMID:35926457 Human UFSP1 is an active protease that regulates UFM1 matura...	ACCEPT	Summary: Independent demonstration that UFSP1 acts in the UFMylation pathway, controlling its activation by maturing UFM1 and cleaving an autoinhibitory modification on the E2 UFC1. Reason: Direct evidence that UFSP1 regulates the UFMylation process; correct BP annotation. Supporting Evidence: PMID:35926457 UFSP1 acts earlier in the pathway to mature UFM1 and cleave a potential autoinhibitory modification on UFC1, thereby controlling activation of UFMylation
GO:0005829 cytosol	IDA PMID:35926457 Human UFSP1 is an active protease that regulates UFM1 matura...	ACCEPT	Summary: Direct subcellular fractionation evidence that endogenous UFSP1 is cytosolic, the compartment in which it acts on UFM1/UFC1. Reason: IDA-supported active-site localization; distinguishes UFSP1 (cytosolic) from the ER-associated UFSP2-mediated RPL26 deUFMylation. Supporting Evidence: PMID:35926457 localization-dependent functions for the two proteases in regulating UFMylation
GO:0008234 cysteine-type peptidase activity	IDA PMID:35525273 Human UFSP1 translated from an upstream near-cognate initiat...	ACCEPT	Summary: UFSP1 is a cysteine (thiol) protease; the active form contains a catalytic Cys protease domain and the Cys-to-Ala mutation abolishes activity. This is the catalytic basis of its UFM1-specific protease activity. Reason: Direct biochemical and mutagenesis evidence establishes UFSP1 as a cysteine-type peptidase; this is the molecular mechanism underlying its deUFMylase activity. Supporting Evidence: PMID:35525273 revealing the presence of a catalytic protease domain containing a Cys active file:human/UFSP1/UFSP1-uniprot.txt C->A: Abolished isopeptidase activity
GO:0008234 cysteine-type peptidase activity	IDA PMID:35926457 Human UFSP1 is an active protease that regulates UFM1 matura...	ACCEPT	Summary: Independent confirmation that UFSP1 is an active cysteine-type protease cleaving UFM1 from substrates. Reason: Corroborates the cysteine-protease mechanism; core molecular function. Supporting Evidence: PMID:35926457 UFSP1 effectively cleaved UFM1 from these different substrates
GO:0051604 protein maturation	IDA PMID:35525273 Human UFSP1 translated from an upstream near-cognate initiat...	ACCEPT	Summary: UFSP1 mediates maturation of the UFM1 precursor (cleaving pro-UFM1 to expose the C-terminal Gly). Protein maturation is a correct, more general BP capturing this processing role. Reason: Pro-UFM1 maturation is a directly demonstrated UFSP1 activity and a prerequisite for UFMylation. Supporting Evidence: PMID:35525273 both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins
GO:0051604 protein maturation	IDA PMID:35926457 Human UFSP1 is an active protease that regulates UFM1 matura...	ACCEPT	Summary: Independent evidence that UFSP1 matures UFM1 (proteolytic processing of pro-UFM1 to expose the C-terminal glycine). Reason: Correct BP annotation for the UFM1-maturation step performed by UFSP1. Supporting Evidence: PMID:35926457 An essential first step in the post-translational modification of proteins with UFM1, UFMylation, is the proteolytic cleavage of pro-UFM1 to expose a C-terminal glycine
GO:0071567 deUFMylase activity	IDA PMID:35525273 Human UFSP1 translated from an upstream near-cognate initiat...	ACCEPT	Summary: Direct demonstration that UFSP1 de-UFMylates target proteins, i.e. removes UFM1 conjugated to substrates. Core molecular function. Reason: deUFMylation of target proteins is directly shown; this is the defining UFSP1 activity. Supporting Evidence: PMID:35525273 both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins
GO:0071567 deUFMylase activity	IDA PMID:35926457 Human UFSP1 is an active protease that regulates UFM1 matura...	ACCEPT	Summary: UFSP1 cleaves UFM1 from diverse substrates and disassembles polyUFM1 chains in vitro, confirming deUFMylase activity. Reason: Direct biochemical evidence for deUFMylase activity; core molecular function. Supporting Evidence: PMID:35926457 UFSP1 effectively cleaved UFM1 from these different substrates

Core Functions

UFM1-specific cysteine (thiol) protease that matures pro-UFM1 by cleaving its C-terminus to expose the activating C-terminal glycine, and removes UFM1 from conjugated substrates (deUFMylation), thereby controlling activation and reversal of UFMylation.

Molecular Function:

deUFMylase activity

Cellular Locations:

cytosol

Supporting Evidence:

PMID:35525273
both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation of target proteins
PMID:35926457
UFSP1 effectively cleaved UFM1 from these different substrates

Cysteine-type peptidase activity (catalytic Cys protease domain) underlying UFSP1's UFM1-specific protease function; the active form arises from a non-canonical upstream start codon.

Molecular Function:

cysteine-type peptidase activity

Cellular Locations:

cytosol

Supporting Evidence:

PMID:35525273
revealing the presence of a catalytic protease domain containing a Cys active
file:human/UFSP1/UFSP1-uniprot.txt
C->A: Abolished isopeptidase activity

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:32296183

A reference map of the human binary protein interactome.

PMID:35525273

Human UFSP1 translated from an upstream near-cognate initiation codon functions as an active UFM1-specific protease.

Human UFSP1 is translated from an upstream near-cognate 217CUG codon (eIF2A-mediated), yielding a form that contains a catalytic protease domain with a Cys active site; the canonical 445AUG form lacks the active site.
Both UFSP1 and UFSP2 mediate maturation of the UFM1 precursor and de-UFMylation of target proteins; mutation of the catalytic cysteine abolishes activity.

PMID:35926457

Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation.

UFSP1 (from a non-canonical start site) is an active protease; cells lacking both UFSPs show complete loss of UFMylation from absence of mature UFM1.
UFSP1 acts early to mature UFM1 and cleave a potential autoinhibitory UFM1 modification on UFC1; unlike UFSP2 it does not remove UFM1 from RPL26. UFSP1 is cytosolic and disassembles polyUFM1 chains in vitro.

Suggested Experiments

Experiment: UFM1-conjugate proteomics in UFSP1-knockout, UFSP2-knockout and double-knockout cells to define non-redundant versus shared deUFMylation substrates.

Experiment: Ribosome profiling / reporter assays to quantify eIF2A-dependent initiation at the 217CUG codon and test how it controls the amount of catalytically active UFSP1.

📚 Additional Documentation

Notes

(UFSP1-notes.md)

UFSP1 (Q6NVU6) research notes

Identity

Ufm1-specific protease 1, peptidase C78 family (MEROPS C78.001), paralog of UFSP2.
Long misannotated as catalytically inactive in humans because the canonical 445AUG-initiated protein lacks the catalytic cysteine/protease domain.

Core function: active UFM1-specific cysteine protease

Two 2022 papers established that the endogenous active UFSP1 is translated from an upstream non-canonical (near-cognate CUG/CTG ~217) start codon, producing a longer ~24 kDa isoform (A0A5F9ZGY7) that contains the catalytic Cys protease domain. PMID:35926457 PMID:35525273
UFSP1 is an active cysteine protease that matures pro-UFM1 (removes the C-terminal Ser-Cys dipeptide to expose the C-terminal Gly) AND de-UFMylates target proteins. PMID:35525273
Catalytic residue: Cys (ACT_SITE 45 in the short-numbered entry; C->A abolishes activity). [UniProt MUTAGEN 45 "C->A: Abolished isopeptidase activity"]

Distinct vs redundant roles (UFSP1 vs UFSP2)

Both contribute redundantly to pro-UFM1 maturation; cells lacking both UFSPs show complete loss of UFMylation due to absence of mature UFM1. PMID:35926457
UFSP2 (ER-localized via ODR4) removes UFM1 from ribosomal RPL26; UFSP1 does NOT reverse RPL26 UFMylation. UFSP1 acts earlier — matures UFM1 and removes a potentially autoinhibitory UFM1 modification on UFC1 (at K122). PMID:35926457
UFSP1 is cytosolic. [UniProt "SUBCELLULAR LOCATION: Cytoplasm, cytosol"] PMID:35926457
In vitro UFSP1 cleaves UFM1 from diverse substrates (UBA5~UFM1, UFC1~UFM1) and disassembles K69-linked polyUFM1 chains. PMID:35926457

Annotation assessment

deUFMylase activity (GO:0071567), cysteine-type peptidase activity (GO:0008234): CORE MF, IDA-supported.
protein maturation (GO:0051604), protein ufmylation (GO:0071569): correct BP context (pro-UFM1 maturation enables UFMylation). Process annotations; keep. ufmylation is the pathway it regulates/enables.
cytosol (GO:0005829): correct localization, IDA + IEA.
protein binding (GO:0005515, PMID:32296183): high-throughput IntAct interactome with ~40 partners (transcription factors etc.), uninformative; no specific functional partner. KEEP_AS_NON_CORE per guidelines.

Pathway step (batch guidance)

UFSP1/UFSP2 = UFM1-specific proteases in the UFMylation cascade (UBA5 E1, UFC1 E2, UFL1 E3, DDRGK1/UFBP1 adaptor). Core MF here is the UFM1-specific/cysteine protease (deUFMylating) activity.

Pn Notes

(UFSP1-pn-notes.md)

UFSP1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q6NVU6
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07c
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/UFSP1/UFSP1-ai-review.yaml
AIGR review HTML: present - genes/human/UFSP1/UFSP1-ai-review.html
Gene notes: present - genes/human/UFSP1/UFSP1-notes.md
GOA TSV: present - genes/human/UFSP1/UFSP1-goa.tsv
UniProt record: present - genes/human/UFSP1/UFSP1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/UFSP1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/UFSP1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: UFSP1 (UFM1-specific protease 1) is a cytosolic thiol-dependent (cysteine-type) isopeptidase of the peptidase C78 family and a paralog of UFSP2. The catalytically active human protein is produced from an upstream near-cognate (217CUG) initiation codon, generating an N-terminally extended form that contains the catalytic Cys protease domain; the previously annotated 445AUG-initiated short form lacks the active site and is inactive. UFSP1 carries out two reactions in the UFM1 (ubiquitin-fold modifier 1) conjugation system - it cleaves pro-UFM1 to expose the C-terminal glycine required for activation (UFM1 maturation), and it removes UFM1 from conjugated substrates (deUFMylation). It acts early in the pathway, maturing UFM1 and removing an autoinhibitory UFM1 modification on the E2 enzyme UFC1, and in vitro disassembles polyUFM1 chains. UFSP1 and UFSP2 act redundantly in pro-UFM1 maturation, but differ in substrate specificity and localization (UFSP2, not UFSP1, deUFMylates the ribosomal subunit RPL26).
Existing/core annotation action counts: ACCEPT: 12; KEEP_AS_NON_CORE: 1

PN Consistency Summary

Consistency: Strong. Deep-research notes, review YAML, PN annotation and PN-node mapping all converge: UFSP1 is an active UFM1-specific cysteine protease (deUFMylase) that matures pro-UFM1 and removes an autoinhibitory UFM1 mark on UFC1; it is cytosolic and (unlike UFSP2) does NOT deUFMylate RPL26. GOA cross-check confirms goa_status: GO:0071567 already-in-GOA (4 records), GO:0071569 already-in-GOA (2), GO:0006515 new-to-GOA (0). No contradictions.
PN story / NEW pressure: PN's deUFMylase + ufmylation story is fully captured by existing annotations (GO:0071567 IDA/IBA, GO:0071569 IDA, GO:0008234, GO:0051604). The one element NOT in GOA is the group-level GO:0006515 (PQC). For UFSP1 this over-reaches: UFSP1 acts on UFM1/UFC1 maturation in the cytosol, not on ribosome-associated QC of misfolded/stalled nascent chains (that arm is UFSP2/RPL26). No defensible NEW term needed; deUFMylase activity already captured.
Evidence alignment: PN row 2 cites PMID:29476094 (Millrine UFSP review) — not in the review YAML, which instead anchors on the two primary 2022 papers (PMID:35525273, PMID:35926457) plus the HuRI interactome (PMID:32296183). Same biology, complementary references; no conflict.
Verdict: Consistent and complete; the only flag is the RQC-group GO:0006515 projection over-reaching for cytosolic UFSP1.

Full Consistency Review

UniProt: Q6NVU6 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
PN placement: two rows — 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 → GO:0071569 protein ufmylation, GO:0071567 deUFMylase activity, plus group-level GO:0006515 PQC for misfolded/incompletely synthesized proteins (from RQC group); UPS class/branch no_mapping.
Consistency: Strong. Deep-research notes, review YAML, PN annotation and PN-node mapping all converge: UFSP1 is an active UFM1-specific cysteine protease (deUFMylase) that matures pro-UFM1 and removes an autoinhibitory UFM1 mark on UFC1; it is cytosolic and (unlike UFSP2) does NOT deUFMylate RPL26. GOA cross-check confirms goa_status: GO:0071567 already-in-GOA (4 records), GO:0071569 already-in-GOA (2), GO:0006515 new-to-GOA (0). No contradictions.
PN story / NEW pressure: PN's deUFMylase + ufmylation story is fully captured by existing annotations (GO:0071567 IDA/IBA, GO:0071569 IDA, GO:0008234, GO:0051604). The one element NOT in GOA is the group-level GO:0006515 (PQC). For UFSP1 this over-reaches: UFSP1 acts on UFM1/UFC1 maturation in the cytosol, not on ribosome-associated QC of misfolded/stalled nascent chains (that arm is UFSP2/RPL26). No defensible NEW term needed; deUFMylase activity already captured.
Mapping strategy: UFSP1 does not change the UPS-side node (correctly anchored on GO:0071567). On the Translation/RQC side, the GROUP→GO:0006515 projection is too broad for UFSP1 specifically (cytosolic UFM1-maturation enzyme, not a misfolded/incomplete-protein degradation factor). Status/scope on the deUFMylase nodes are right.
Evidence alignment: PN row 2 cites PMID:29476094 (Millrine UFSP review) — not in the review YAML, which instead anchors on the two primary 2022 papers (PMID:35525273, PMID:35926457) plus the HuRI interactome (PMID:32296183). Same biology, complementary references; no conflict.
Verdict: Consistent and complete; the only flag is the RQC-group GO:0006515 projection over-reaching for cytosolic UFSP1.

Recommended edits: [MAP] do not project group-level GO:0006515 (PQC for misfolded/incompletely synthesized proteins) onto UFSP1 — UFSP1 is a cytosolic UFM1-maturation/deUFMylase enzyme, not a ribosome-associated misfolded-protein QC factor (contrast UFSP2/RPL26).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07c
review_yaml: genes/human/UFSP1/UFSP1-ai-review.yaml
PN workbook rows: 2

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

UniProt: Q6NVU6
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: Q6NVU6
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=already_in_goa_exact | 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.

📄 View Raw YAML

id: Q6NVU6
gene_symbol: UFSP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UFSP1 (UFM1-specific protease 1) is a cytosolic thiol-dependent (cysteine-type)
  isopeptidase of the peptidase C78 family and a paralog of UFSP2. The catalytically
  active human protein is produced from an upstream near-cognate (217CUG) initiation
  codon, generating an N-terminally extended form that contains the catalytic Cys
  protease domain; the previously annotated 445AUG-initiated short form lacks the
  active site and is inactive. UFSP1 carries out two reactions in the UFM1 (ubiquitin-fold
  modifier 1) conjugation system - it cleaves pro-UFM1 to expose the C-terminal glycine
  required for activation (UFM1 maturation), and it removes UFM1 from conjugated substrates
  (deUFMylation). It acts early in the pathway, maturing UFM1 and removing an autoinhibitory
  UFM1 modification on the E2 enzyme UFC1, and in vitro disassembles polyUFM1 chains.
  UFSP1 and UFSP2 act redundantly in pro-UFM1 maturation, but differ in substrate
  specificity and localization (UFSP2, not UFSP1, deUFMylates the ribosomal subunit
  RPL26).
existing_annotations:
- 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
      across the UFSP family. This is the core molecular function of UFSP1 and is directly
      supported by experimental evidence for the human protein.
    action: ACCEPT
    reason: deUFMylase activity is the central, experimentally confirmed function of
      UFSP1; the IBA call is corroborated by direct biochemical assays.
    supported_by:
    - reference_id: PMID:35525273
      supporting_text: both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation
        of target proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic localization to cytosol, consistent with the experimentally
      determined cytosolic localization of UFSP1.
    action: ACCEPT
    reason: Cytosol is the documented site of UFSP1 action; the IEA call agrees with
      direct subcellular fractionation evidence.
    supported_by:
    - reference_id: file:human/UFSP1/UFSP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary (Y2H) human interactome screen recording ~40 partners
      (largely transcription factors and unrelated proteins). The bare protein binding
      term is uninformative and the partners do not converge on a coherent UFSP1 function.
    action: KEEP_AS_NON_CORE
    reason: Records real binary interactions but the generic term carries no functional
      information and the partners are not part of UFSP1's UFM1-protease function;
      retained as non-core per curation guidelines on protein binding.
    supported_by:
    - reference_id: file:human/UFSP1/UFSP1-goa.tsv
      supporting_text: GO:0005515
- 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 the experimentally supported IDA annotations.
    action: ACCEPT
    reason: Correct core molecular function; agrees with stronger experimental evidence.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: UFSP1 effectively cleaved UFM1 from these different substrates
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:35525273
  qualifier: involved_in
  review:
    summary: UFSP1 is involved in protein UFMylation by maturing pro-UFM1, a prerequisite
      for conjugation, and by reversing UFM1 conjugation. This is the correct biological-process
      context for its protease activity.
    action: ACCEPT
    reason: By generating mature UFM1 and removing an autoinhibitory UFM1 mark on UFC1,
      UFSP1 directly controls the activation of the UFMylation pathway.
    supported_by:
    - reference_id: PMID:35525273
      supporting_text: both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation
        of target proteins
- term:
    id: GO:0071569
    label: protein ufmylation
  evidence_type: IDA
  original_reference_id: PMID:35926457
  qualifier: involved_in
  review:
    summary: Independent demonstration that UFSP1 acts in the UFMylation pathway, controlling
      its activation by maturing UFM1 and cleaving an autoinhibitory modification on
      the E2 UFC1.
    action: ACCEPT
    reason: Direct evidence that UFSP1 regulates the UFMylation process; correct BP
      annotation.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: UFSP1 acts earlier in the pathway to mature UFM1 and cleave
        a potential autoinhibitory modification on UFC1, thereby controlling activation
        of UFMylation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:35926457
  qualifier: is_active_in
  review:
    summary: Direct subcellular fractionation evidence that endogenous UFSP1 is cytosolic,
      the compartment in which it acts on UFM1/UFC1.
    action: ACCEPT
    reason: IDA-supported active-site localization; distinguishes UFSP1 (cytosolic)
      from the ER-associated UFSP2-mediated RPL26 deUFMylation.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: localization-dependent functions for the two proteases in regulating
        UFMylation
- term:
    id: GO:0008234
    label: cysteine-type peptidase activity
  evidence_type: IDA
  original_reference_id: PMID:35525273
  qualifier: enables
  review:
    summary: UFSP1 is a cysteine (thiol) protease; the active form contains a catalytic
      Cys protease domain and the Cys-to-Ala mutation abolishes activity. This is the
      catalytic basis of its UFM1-specific protease activity.
    action: ACCEPT
    reason: Direct biochemical and mutagenesis evidence establishes UFSP1 as a cysteine-type
      peptidase; this is the molecular mechanism underlying its deUFMylase activity.
    supported_by:
    - reference_id: PMID:35525273
      supporting_text: revealing the presence of a catalytic protease domain containing
        a Cys active
    - reference_id: file:human/UFSP1/UFSP1-uniprot.txt
      supporting_text: 'C->A: Abolished isopeptidase activity'
- term:
    id: GO:0008234
    label: cysteine-type peptidase activity
  evidence_type: IDA
  original_reference_id: PMID:35926457
  qualifier: enables
  review:
    summary: Independent confirmation that UFSP1 is an active cysteine-type protease
      cleaving UFM1 from substrates.
    action: ACCEPT
    reason: Corroborates the cysteine-protease mechanism; core molecular function.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: UFSP1 effectively cleaved UFM1 from these different substrates
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:35525273
  qualifier: involved_in
  review:
    summary: UFSP1 mediates maturation of the UFM1 precursor (cleaving pro-UFM1 to
      expose the C-terminal Gly). Protein maturation is a correct, more general BP
      capturing this processing role.
    action: ACCEPT
    reason: Pro-UFM1 maturation is a directly demonstrated UFSP1 activity and a prerequisite
      for UFMylation.
    supported_by:
    - reference_id: PMID:35525273
      supporting_text: both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation
        of target proteins
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:35926457
  qualifier: involved_in
  review:
    summary: Independent evidence that UFSP1 matures UFM1 (proteolytic processing of
      pro-UFM1 to expose the C-terminal glycine).
    action: ACCEPT
    reason: Correct BP annotation for the UFM1-maturation step performed by UFSP1.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: An essential first step in the post-translational modification
        of proteins with UFM1, UFMylation, is the proteolytic cleavage of pro-UFM1
        to expose a C-terminal glycine
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:35525273
  qualifier: enables
  review:
    summary: Direct demonstration that UFSP1 de-UFMylates target proteins, i.e. removes
      UFM1 conjugated to substrates. Core molecular function.
    action: ACCEPT
    reason: deUFMylation of target proteins is directly shown; this is the defining
      UFSP1 activity.
    supported_by:
    - reference_id: PMID:35525273
      supporting_text: both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation
        of target proteins
- term:
    id: GO:0071567
    label: deUFMylase activity
  evidence_type: IDA
  original_reference_id: PMID:35926457
  qualifier: enables
  review:
    summary: UFSP1 cleaves UFM1 from diverse substrates and disassembles polyUFM1 chains
      in vitro, confirming deUFMylase activity.
    action: ACCEPT
    reason: Direct biochemical evidence for deUFMylase activity; core molecular function.
    supported_by:
    - reference_id: PMID:35926457
      supporting_text: UFSP1 effectively cleaved UFM1 from these different substrates
references:
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- 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 map (HuRI); records ~40 UFSP1
      interactors but none informs the UFM1-protease function.
- id: PMID:35525273
  title: Human UFSP1 translated from an upstream near-cognate initiation codon functions
    as an active UFM1-specific protease.
  findings:
  - statement: Human UFSP1 is translated from an upstream near-cognate 217CUG codon
      (eIF2A-mediated), yielding a form that contains a catalytic protease domain
      with a Cys active site; the canonical 445AUG form lacks the active site.
    reference_section_type: ABSTRACT
  - statement: Both UFSP1 and UFSP2 mediate maturation of the UFM1 precursor and de-UFMylation
      of target proteins; mutation of the catalytic cysteine abolishes activity.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; establishes human UFSP1 as an active UFM1-specific
      cysteine protease.
- id: PMID:35926457
  title: Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation.
  findings:
  - statement: UFSP1 (from a non-canonical start site) is an active protease; cells
      lacking both UFSPs show complete loss of UFMylation from absence of mature UFM1.
    reference_section_type: ABSTRACT
  - statement: UFSP1 acts early to mature UFM1 and cleave a potential autoinhibitory
      UFM1 modification on UFC1; unlike UFSP2 it does not remove UFM1 from RPL26. UFSP1
      is cytosolic and disassembles polyUFM1 chains in vitro.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; defines distinct substrate specificity and cytosolic
      localization of UFSP1 vs UFSP2.
core_functions:
- description: UFM1-specific cysteine (thiol) protease that matures pro-UFM1 by cleaving
    its C-terminus to expose the activating C-terminal glycine, and removes UFM1 from
    conjugated substrates (deUFMylation), thereby controlling activation and reversal
    of UFMylation.
  molecular_function:
    id: GO:0071567
    label: deUFMylase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:35525273
    supporting_text: both UFSP1 and UFSP2 mediate maturation of UFM1 and de-UFMylation
      of target proteins
  - reference_id: PMID:35926457
    supporting_text: UFSP1 effectively cleaved UFM1 from these different substrates
- description: Cysteine-type peptidase activity (catalytic Cys protease domain) underlying
    UFSP1's UFM1-specific protease function; the active form arises from a non-canonical
    upstream start codon.
  molecular_function:
    id: GO:0008234
    label: cysteine-type peptidase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:35525273
    supporting_text: revealing the presence of a catalytic protease domain containing
      a Cys active
  - reference_id: file:human/UFSP1/UFSP1-uniprot.txt
    supporting_text: 'C->A: Abolished isopeptidase activity'
proposed_new_terms: []
suggested_questions:
- question: What is the full physiological substrate repertoire of UFSP1 deUFMylation
    beyond UFC1, and how does it partition with UFSP2 in vivo?
- question: How is the non-canonical 217CUG translation of the active UFSP1 isoform
    regulated, and does its abundance limit UFMylation flux under stress?
suggested_experiments:
- description: UFM1-conjugate proteomics in UFSP1-knockout, UFSP2-knockout and double-knockout
    cells to define non-redundant versus shared deUFMylation substrates.
- description: Ribosome profiling / reporter assays to quantify eIF2A-dependent initiation
    at the 217CUG codon and test how it controls the amount of catalytically active
    UFSP1.

UFSP1

Gene Description