# OTUD3 (Q5T2D3) research notes

## Summary
OTUD3 (OTU domain-containing protein 3) is a cysteine-protease deubiquitinase (DUB, EC 3.4.19.12) of the ovarian tumor (OTU) family. Its catalytic OTU domain (active-site nucleophile Cys76, with His182) hydrolyzes isopeptide bonds of ubiquitin chains with a preference for atypical Lys-6 (K6)- and Lys-11 (K11)-linked polyubiquitin, and it also processes heterotypic (mixed/branched) and other homotypic chains; a C-terminal UBA-like domain does not affect catalysis. OTUD3 acts on specific substrates: it deubiquitinates and stabilizes the tumor suppressor PTEN (suppressing PI3K-AKT signaling and tumorigenesis), stabilizes the nuclear receptor PPARD to regulate glucose and lipid metabolism and oxidative phosphorylation in response to nutritional stress (with glucose/fatty-acid-triggered, CBP/CREBBP-dependent acetylation driving its nuclear translocation), and deubiquitinates KPTN to suppress mTORC1 signaling. In ribosome-associated quality control, OTUD3 acts as a negative regulator by deubiquitinating 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, antagonizing ZNF598-mediated 40S ubiquitination. OTUD3 shuttles between the cytoplasm and the nucleus.

## Core functions (from review)
- **GO:0004843 cysteine-type deubiquitinase activity** — OTU-family cysteine-protease deubiquitinase that hydrolyzes ubiquitin isopeptide bonds with a preference for atypical Lys-6- and Lys-11-linked polyubiquitin chains (also heterotypic/branched chains), via its OTU domain (catalytic Cys76).
- **GO:0004843 cysteine-type deubiquitinase activity** — Substrate-specific deubiquitinase that stabilizes target proteins by removing degradative ubiquitin, including PTEN (suppressing PI3K-AKT signaling), PPARD (regulating metabolism in response to nutritional stress), and KPTN (suppressing mTORC1), and that deubiquitinates 40S ribosomal proteins to negatively regulate ribosome-associated quality control.

## Provenance
Research and verbatim supporting quotes are recorded inline in `OTUD3-ai-review.yaml` (per-annotation `supported_by` and `references` findings). This notes file summarizes the completed review; see the YAML for evidence citations.