The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The UniProt accession Q7T347 corresponds to Danio rerio ufsp2, annotated as Ufm1-specific protease 2 (UfSP2), a cysteine protease in the UFMylation (UFM1 conjugation) system. In the retrieved literature corpus, “UFSP2/Ufsp2” consistently refers to the UFM1-specific protease 2 (not an unrelated gene), functioning as a UFM1-directed deconjugating enzyme and pro-UFM1 maturase, typically positioned at the endoplasmic reticulum (ER) through interaction with ODR4. (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 4-5)
Important evidence limitation: despite targeted searches, direct zebrafish (Danio rerio) primary studies specifically on ufsp2 (Q7T347; zgc:64113) were not recovered in this tool run. Accordingly, zebrafish ufsp2 function below is annotated primarily via conserved orthology and cross-species mechanistic studies (mainly human/mouse cells) and is clearly labeled as such. (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 4-5)
UFMylation is a ubiquitin-like post-translational modification in which the ubiquitin-fold modifier UFM1 is covalently attached to lysine residues of protein substrates through an E1–E2–E3 cascade. This pathway has been strongly linked to ER-associated functions, particularly ribosome quality control and ER proteostasis. (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22)
The UFMylation pathway is regulated by UFM1-specific proteases (UFSP1 and UFSP2) that perform two central reactions:
1. pro-UFM1 maturation (processing the UFM1 precursor to expose the C-terminal glycine required for conjugation), and
2. de-UFMylation (isopeptidase activity removing UFM1 from substrates). (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22)
A key mechanistic detail is that pro-UFM1 activation requires removal of a Ser84–Cys85 dipeptide to expose the conjugatable UFM1 C-terminus. (millrine2023aguideto pages 2-4)
UFSP2 is described as a UFM1-specific cysteine protease/isopeptidase, with activity dependent on a catalytic cysteine and a conserved Cys–Asp–His catalytic triad (often discussed alongside an additional conserved Tyr typical of cysteine-based Ub/UBL proteases). UFSP activity can be inhibited by thiol-reactive reagents such as N-ethylmaleimide (NEM) or by mutation of the catalytic cysteine. (zhou2024ufmylationaubiquitinlike pages 19-22)
Cross-species evidence supports that UFSP2 catalyzes:
- Proteolytic maturation of pro-UFM1 to mature UFM1 required for UFMylation, and
- Hydrolysis of isopeptide bonds linking UFM1 to substrate proteins (de-UFMylation). (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22)
Recent synthesis of mechanistic work supports a functional partitioning:
- UFSP2: a major de-UFMylase for ER-associated substrates, particularly efficiently removing UFM1 from the ribosomal protein RPL26 (uL24); UFSP2 knockout causes a drastic accumulation of UFMylated proteins in cell systems summarized in reviews. (zhou2024ufmylationaubiquitinlike pages 19-22)
- UFSP1: more efficient for pro-UFM1 maturation and for removing UFM1 from the E2 enzyme UFC1 at Lys122 (a site near UFC1 catalytic Cys116), consistent with a role in maintaining UFMylation flux. (zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 2-4)
This division-of-labor model is central to interpreting zebrafish ufsp2: if conserved, zebrafish Ufsp2 would be expected to primarily tune ER/ribosome-associated de-UFMylation, especially on ribosomal targets like Rpl26/uL24. (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 4-5)
A consistent mechanistic conclusion is that UFSP2 is positioned at the endoplasmic reticulum via an interaction with ODR4, an ER membrane protein. UFSP2 is commonly described as ER-associated/tethered rather than intrinsically membrane-spanning, and loss of one partner can destabilize the other in the ER-tethering model summarized in reviews. (millrine2023aguideto pages 4-5, komatsu2025ufm1atthe pages 1-2)
In the current pathway-centric view, this ER tethering spatially matches UFSP2 to major UFMylation events on ER-associated ribosomes, and thus to ER proteostasis/ribosome quality control processes. (millrine2023aguideto pages 2-4, millrine2023aguideto pages 4-5)
Multiple 2023–2024 sources emphasize that UFMylation is strongly engaged at the ER and that RPL26/uL24 is a principal UFMylation target in cells, especially in contexts of translational stalling and ER translocon stress; UFSP2 is positioned as the counteracting de-UFMylase. (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 4-5)
A 2024 Nature study (“UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER”) provides primary, high-authority support for a model in which UFMylation machinery promotes recycling of 60S ribosomal subunits from ER-associated states, and it explicitly frames UFSP2 as an ER-tethered UFM1-specific hydrolase in this functional context. (darosa2024ufm1e3ligase pages 1-6)
No directly retrieved primary study in this run measured zebrafish ufsp2 (Q7T347) enzymatic activity, localization, developmental expression, or knockout phenotype. Therefore, any zebrafish-specific statements about ufsp2 beyond orthology-based inference cannot be made from the present evidence set. (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22)
A human genetics study on UBA5 (the UFM1 E1 enzyme) reported zebrafish experiments in which uba5 silencing decreased motility and induced abnormal movements suggestive of seizures, supporting that perturbing the UFMylation pathway has measurable neurobehavioral consequences in zebrafish. However, this is not ufsp2-specific; it supports pathway importance in zebrafish rather than attributing a phenotype to ufsp2. (colin2016biallelicvariantsin pages 1-2)
Millrine et al. (FEBS Journal, publication date: Feb 2023) emphasized that RPL26/uL24 is one of the main targets of UFMylation in cells and described the UFMylation pathway as operating at the ER in coordination with ribosome quality control. This review also summarized then-recent evidence that human UFSP1 is catalytically active (via non-canonical translation initiation) and that ER-associated UFSP2 (via ODR4) is positioned to regulate ribosome-linked UFMylation. (millrine2023aguideto pages 2-4, millrine2023aguideto pages 4-5)
Zhou et al. (Trends in Biochemical Sciences, publication date: Jan 2024) provided an authoritative synthesis (“Box 1”) that UFSP2 knockout causes drastic accumulation of UFMylated proteins, and that UFSP2 efficiently removes UFMylation from RPL26, whereas UFSP1 is more efficient for pro-UFM1 maturation and UFC1 Lys122 de-UFMylation. This is a current expert consensus-like framing of UFSP2’s core biochemical niche. (zhou2024ufmylationaubiquitinlike pages 19-22)
DaRosa et al. (Nature, publication date: Feb 2024) provides high-impact primary evidence that the UFM1 system is mechanistically involved in 60S ribosome recycling from the ER, and frames UFSP2 as an ER-tethered UFM1 hydrolase in this process context—strengthening the interpretation that UFSP2’s key physiological substrates are ER-proximal ribosomal UFMylation targets. (darosa2024ufm1e3ligase pages 1-6)
Although zebrafish-specific ufsp2 disease models were not identified here, UFSP2’s pathway is medically relevant because defects in UFMylation components (including UFSP2 in broader literature) are associated with human developmental and neurological phenotypes and have become an emerging target space for understanding ER proteostasis defects. The strongest mechanistic-to-application bridge in the retrieved set is that the UFMylation system is now understood as a regulator of ER ribosome homeostasis, a process broadly implicated in proteostasis-associated disorders. (zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 2-4, darosa2024ufm1e3ligase pages 1-6)
The UFSP enzymes’ UFM1 specificity has enabled use of UFM1 activity-based probes (e.g., UFM1-VME) in biochemical studies to capture UFSP activity and define protease specificity, supporting pathway-mapping and mechanistic dissection that can be adapted to non-mammalian orthologs such as zebrafish ufsp2. (millrine2023aguideto pages 2-4)
The following table consolidates the most supportable functional annotation elements for zebrafish ufsp2 (Q7T347), explicitly separating conserved mechanistic evidence from the limited direct zebrafish evidence.
| Aspect | Key points | Evidence type (review/primary) | Best citation IDs (pqac-...) | Publication (first author year journal) | URL/DOI |
|---|---|---|---|---|---|
| Identity/orthology | Target is zebrafish ufsp2 / Ufm1-specific protease 2 (UniProt Q7T347), a peptidase C78 family member. Direct zebrafish-specific primary literature is sparse, so functional annotation relies substantially on conserved cross-species UFSP2/UFMylation evidence plus UniProt/domain context. | Review + database-informed inference | (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22) | Millrine 2023 FEBS J; Zhou 2024 Trends Biochem Sci | https://doi.org/10.1111/febs.16730 ; https://doi.org/10.1016/j.tibs.2023.10.004 |
| Enzymatic activity | UFSP2 is a UFM1-specific cysteine protease/deUFMylase. It catalyzes both pro-UFM1 maturation and removal of UFM1 from modified proteins, although current understanding emphasizes stronger de-UFMylase/substrate-editing roles for UFSP2 compared with UFSP1 in many mammalian systems. | Review | (wang2023theposttranslationalrole pages 2-4, millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22) | Wang 2023 Cells; Millrine 2023 FEBS J; Zhou 2024 Trends Biochem Sci | https://doi.org/10.3390/cells12212543 ; https://doi.org/10.1111/febs.16730 ; https://doi.org/10.1016/j.tibs.2023.10.004 |
| Reaction catalyzed | Proteolytic cleavage of the C-terminal extension of pro-UFM1 exposes the terminal glycine required for conjugation; UFSP2 also hydrolyzes isopeptide bonds linking UFM1 to substrate lysines (de-UFMylation). UFSP catalytic activity depends on a conserved Cys-Asp-His catalytic core/triad. | Review | (kuang2026theufm1conjugation pages 4-5, zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 2-4) | Kuang 2026 Biology; Zhou 2024 Trends Biochem Sci; Zhou 2024 accepted manuscript; Millrine 2023 FEBS J | https://doi.org/10.3390/biology15050382 ; https://doi.org/10.1016/j.tibs.2023.10.004 ; https://doi.org/10.1111/febs.16730 |
| Substrate specificity | UFSP2 is reported to efficiently de-UFMylate RPL26/uL24 on ER-associated ribosomes; UFSP1 instead shows stronger roles in pro-UFM1 maturation and removing UFM1 from UFC1 Lys122. UFSP2 can also reverse UFMylation on model substrates such as DDRGK1/UFBP1 and ASC1 in vitro/cell studies. | Review summarizing primary studies | (kuang2026theufm1conjugation pages 5-7, millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22, kuang2026theufm1conjugation pages 4-5) | Kuang 2026 Biology; Millrine 2023 FEBS J; Zhou 2024 Trends Biochem Sci | https://doi.org/10.3390/biology15050382 ; https://doi.org/10.1111/febs.16730 ; https://doi.org/10.1016/j.tibs.2023.10.004 |
| Localization | UFSP2 is primarily positioned at the endoplasmic reticulum (ER) through association with the tail-anchored factor ODR4; its extended N-terminus contributes to ER localization and substrate selectivity. Some reviews also list nucleus/cytoplasm/ER localization, but ER tethering is the strongest mechanistic conclusion. | Review | (kuang2026theufm1conjugation pages 5-7, kuang2026theufm1conjugation pages 4-5, millrine2023aguideto pages 4-5, komatsu2025ufm1atthe pages 1-2) | Kuang 2026 Biology; Millrine 2023 FEBS J; Komatsu 2025 Essays Biochem | https://doi.org/10.3390/biology15050382 ; https://doi.org/10.1111/febs.16730 ; https://doi.org/10.1042/ebc20253054 |
| Pathway role | UFSP2 functions in the UFMylation/de-UFMylation pathway, especially at the ER where it helps regulate ribosome quality control, ER homeostasis, and likely ER-phagy-associated processes by editing ribosome-linked UFM1 signals. | Review | (kuang2026theufm1conjugation pages 5-7, millrine2023aguideto pages 2-4, komatsu2025ufm1atthe pages 1-2) | Kuang 2026 Biology; Millrine 2023 FEBS J; Komatsu 2025 Essays Biochem | https://doi.org/10.3390/biology15050382 ; https://doi.org/10.1111/febs.16730 ; https://doi.org/10.1042/ebc20253054 |
| Zebrafish evidence / phenotypes | Zebrafish-specific evidence for ufsp2 itself is limited in the retrieved sources. A 2016 human-disease paper used zebrafish to model uba5 deficiency, not ufsp2, showing reduced motility and abnormal seizure-like movements after uba5 silencing; this supports pathway importance in vertebrate neurobiology but is not direct ufsp2 functional evidence. | Primary (pathway-level, not ufsp2-specific) | (colin2016biallelicvariantsin pages 1-2) | Colin 2016 Am J Hum Genet | https://doi.org/10.1016/j.ajhg.2016.06.030 |
| Recent 2023-2024 developments | 2023-2024 literature clarified a division of labor between UFSP1 and UFSP2, resolved the long-standing issue that human UFSP1 can be active, and strengthened the model that ER-tethered UFSP2 edits ribosome UFMylation, especially on RPL26/uL24. A 2024 Nature study further linked UFM1 machinery to recycling of 60S ribosomal subunits from the ER. | Review + primary | (millrine2023aguideto pages 2-4, zhou2024ufmylationaubiquitinlike pages 19-22, darosa2024ufm1e3ligase pages 1-6) | Millrine 2023 FEBS J; Zhou 2024 Trends Biochem Sci; DaRosa 2024 Nature | https://doi.org/10.1111/febs.16730 ; https://doi.org/10.1016/j.tibs.2023.10.004 ; https://doi.org/10.1038/s41586-024-07073-0 |
Table: This table summarizes the best-supported functional annotation for zebrafish ufsp2 (UniProt Q7T347), distinguishing conserved cross-species mechanistic evidence from the limited direct zebrafish literature. It is useful for quickly identifying UFSP2's enzymatic role, substrates, localization, pathway context, and where evidence gaps remain.
Given the evidence base available here, the most defensible functional annotation for Danio rerio ufsp2 (Q7T347) is:
- Molecular function (inferred by orthology): UFM1-specific cysteine protease (peptidase C78 family) acting as a de-UFMylase and pro-UFM1 maturase, with the dominant cellular role likely being de-UFMylation of ER-proximal substrates including UFMylated ribosomal proteins (RPL26/uL24). (millrine2023aguideto pages 4-5, zhou2024ufmylationaubiquitinlike pages 19-22, millrine2023aguideto pages 2-4)
- Cellular component (inferred by orthology): ER-associated via ODR4 tethering, aligning UFSP2 activity to ER ribosome quality control and ER proteostasis. (millrine2023aguideto pages 4-5, komatsu2025ufm1atthe pages 1-2)
- Biological process (inferred by pathway conservation): regulation of ER homeostasis and ribosome-associated quality control through dynamic editing of UFMylation on ribosomes and ER-localized pathway components. (millrine2023aguideto pages 2-4, darosa2024ufm1e3ligase pages 1-6)
References
(millrine2023aguideto pages 2-4): David Millrine, Joshua J. Peter, and Yogesh Kulathu. A guide to ufmylation, an emerging posttranslational modification. The FEBS Journal, 290:5040-5056, Feb 2023. URL: https://doi.org/10.1111/febs.16730, doi:10.1111/febs.16730. This article has 71 citations.
(zhou2024ufmylationaubiquitinlike pages 19-22): Xingchen Zhou, Sayyed J. Mahdizadeh, Matthieu Le Gallo, Leif A. Eriksson, Eric Chevet, and Elodie Lafont. Ufmylation: a ubiquitin-like modification. Trends in Biochemical Sciences, 49:52-67, Jan 2024. URL: https://doi.org/10.1016/j.tibs.2023.10.004, doi:10.1016/j.tibs.2023.10.004. This article has 82 citations and is from a domain leading peer-reviewed journal.
(millrine2023aguideto pages 4-5): David Millrine, Joshua J. Peter, and Yogesh Kulathu. A guide to ufmylation, an emerging posttranslational modification. The FEBS Journal, 290:5040-5056, Feb 2023. URL: https://doi.org/10.1111/febs.16730, doi:10.1111/febs.16730. This article has 71 citations.
(komatsu2025ufm1atthe pages 1-2): Masaaki Komatsu and Gaoxin Mao. Ufm1 at the endoplasmic reticulum: linking er stress, ribosome quality control, and er-phagy. Essays in Biochemistry, 69:281-290, Oct 2025. URL: https://doi.org/10.1042/ebc20253054, doi:10.1042/ebc20253054. This article has 3 citations and is from a peer-reviewed journal.
(darosa2024ufm1e3ligase pages 1-6): Paul A. DaRosa, Ivan Penchev, Samantha C. Gumbin, Francesco Scavone, Magda Wąchalska, Joao A. Paulo, Alban Ordureau, Joshua J. Peter, Yogesh Kulathu, J. Wade Harper, Thomas Becker, Roland Beckmann, and Ron R. Kopito. Ufm1 e3 ligase promotes recycling of 60s ribosomal subunits from the er. Nature, 627:445-452, Feb 2024. URL: https://doi.org/10.1038/s41586-024-07073-0, doi:10.1038/s41586-024-07073-0. This article has 62 citations and is from a highest quality peer-reviewed journal.
(colin2016biallelicvariantsin pages 1-2): Estelle Colin, Jens Daniel, Alban Ziegler, Jamal Wakim, Aurora Scrivo, Tobias B. Haack, Salim Khiati, Anne-Sophie Denommé, Patrizia Amati-Bonneau, Majida Charif, Vincent Procaccio, Pascal Reynier, Kyrieckos A. Aleck, Lorenzo D. Botto, Claudia Lena Herper, Charlotte Sophia Kaiser, Rima Nabbout, Sylvie N’Guyen, José Antonio Mora-Lorca, Birgit Assmann, Stine Christ, Thomas Meitinger, Tim M. Strom, Holger Prokisch, Antonio Miranda-Vizuete, Georg F. Hoffmann, Guy Lenaers, Pascale Bomont, Eva Liebau, Dominique Bonneau, Emmanuelle Génin, Dominique Campion, Jean-François Dartigues, Jean-François Deleuze, Jean-Charles Lambert, Richard Redon, Thomas Ludwig, Benjamin Grenier-Boley, Sébastien Letort, Pierre Lindenbaum, Vincent Meyer, Olivier Quenez, Christian Dina, Céline Bellenguez, Camille Charbonnier -Le Clézio, Joanna Giemza, Stéphanie Chatel, Claude Férec, Hervé Le Marec, Luc Letenneur, Gaël Nicolas, Karen Rouault, Delphine Bacq, Anne Boland, and Doris Lechner. Biallelic variants in uba5 reveal that disruption of the ufm1 cascade can result in early-onset encephalopathy. American journal of human genetics, 99 3:695-703, Sep 2016. URL: https://doi.org/10.1016/j.ajhg.2016.06.030, doi:10.1016/j.ajhg.2016.06.030. This article has 131 citations and is from a highest quality peer-reviewed journal.
(wang2023theposttranslationalrole pages 2-4): Xingde Wang, Xingzhi Xu, and Zhifeng Wang. The post-translational role of ufmylation in physiology and disease. Cells, 12:2543, Oct 2023. URL: https://doi.org/10.3390/cells12212543, doi:10.3390/cells12212543. This article has 27 citations.
(kuang2026theufm1conjugation pages 4-5): Meiqian Kuang, Haigang Xu, Hongjun Huang, Caifang Ren, Pan Huang, and Aihua Gong. The ufm1 conjugation system: a master regulator of cellular stress surveillance in human disease. Biology, 15(5):382, Feb 2026. URL: https://doi.org/10.3390/biology15050382, doi:10.3390/biology15050382. This article has 0 citations.
(kuang2026theufm1conjugation pages 5-7): Meiqian Kuang, Haigang Xu, Hongjun Huang, Caifang Ren, Pan Huang, and Aihua Gong. The ufm1 conjugation system: a master regulator of cellular stress surveillance in human disease. Biology, 15(5):382, Feb 2026. URL: https://doi.org/10.3390/biology15050382, doi:10.3390/biology15050382. This article has 0 citations.