OTULIN (OTU Deubiquitinase with Linear Linkage Specificity) is a member of the ovarian tumor (OTU) family of deubiquitinases (DUBs) that exhibits unique specificity for linear (Met1-linked) ubiquitin chains. Originally named FAM105B or OTULIN, this enzyme plays a critical role in regulating the linear ubiquitin chain assembly complex (LUBAC) and downstream NF-κB signaling pathways. Recent research has revealed that OTULIN also regulates tau expression and RNA metabolism in neurons, linking linear ubiquitination to tauopathy pathogenesis in neurodegenerative diseases.
| Symbol | OTULIN |
|---|---|
| Full Name | OTU Deubiquitinase with Linear Linkage Specificity |
| Aliases | OTULIN, FAM105B, OTUD5 |
| Chromosomal Location | Chr5p15.2 |
| NCBI Gene ID | 94025 |
| OMIM | 607737 |
| Ensembl ID | ENSG00000135547 |
| UniProt ID | Q96MS9 |
| Associated Diseases | Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Neurodevelopmental disorders |
OTULIN is a cysteine protease that catalyzes the removal of linear (Met1-linked) ubiquitin chains from substrate proteins. Unlike other OTU family members, OTULIN shows exceptional specificity for linear ubiquitin chains and does not efficiently cleave other ubiquitin linkage types. [1]
The OTULIN protein contains an N-terminal OTU catalytic domain and a C-terminal region involved in protein-protein interactions. The catalytic OTU domain adopts a fold similar to other OTU family members but contains unique structural features that confer linear linkage specificity. The protein interacts with the LUBAC complex through its PUB domain-interacting region. [1:1]
Recent research has identified a novel pathway linking OTULIN-mediated linear ubiquitination to tau expression regulation: [2:2]
Beyond direct transcription effects, OTULIN also regulates RNA metabolism in neurons. Linear ubiquitin chains regulate RNA-binding proteins and splicing factors, which control mRNA stability and translation. Dysregulated RNA metabolism contributes to tau pathology through impaired protein homeostasis. [2:3]
OTULIN belongs to the OTU family of deubiquitinases, which includes:
| Gene | Aliases | Linkage Specificity | Key Functions |
|---|---|---|---|
| OTULIN | FAM105B | Linear (Met1) | LUBAC regulation, NF-κB, tau |
| OTUD1 | OTUD1 | K11, K48 | DNA damage response |
| OTUD3 | OTUD3 | K63, K27 | Stress response, p53 regulation |
| OTUD4 | DUBA | K48, K63 | DNA repair, neuroprotection |
| OTUD5 | OTUD5 | K48, K63 | Transcription regulation, stress |
See also: OTU Deubiquitinase Family