# 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** — 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** — 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.