| 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 | (pqac-00000003, pqac-00000005) | 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 | (pqac-00000000, pqac-00000003, pqac-00000005) | 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 | (pqac-00000002, pqac-00000005, pqac-00000011, pqac-00000012) | 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 | (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000007, pqac-00000009) | 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 | (pqac-00000001, pqac-00000002, pqac-00000006, pqac-00000010) | 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 | (pqac-00000001, pqac-00000003, pqac-00000010, pqac-00000012) | 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) | (pqac-00000014) | 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 | (pqac-00000003, pqac-00000005, pqac-00000007, pqac-00000015) | 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.*