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).
| 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 |
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Download this section (compressed HTML)Q: What is the full physiological substrate repertoire of UFSP1 deUFMylation beyond UFC1, and how does it partition with UFSP2 in vivo?
Q: How is the non-canonical 217CUG translation of the active UFSP1 isoform regulated, and does its abundance limit UFMylation flux under stress?
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.
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