Ubiquitin thioesterase otulin (OTULIN)

Ubiquitin thioesterase otulin (OTULIN) is a highly specific deubiquitinating enzyme belonging to the OTU (ovarian tumor) protease family. OTULIN cleaves only Met1-linked (linear) polyubiquitin chains, distinguishing it from most other DUBs that target isopeptide (Lys-linked) chains. Its specificity arises from a unique OTU domain with a Cys129/His339/Asn341 catalytic triad, activated through substrate-assisted catalysis involving a key Glu16 residue on ubiquitin. OTULIN strictly regulates inflammatory and apoptotic signaling in response to activation of receptors such as TNFR1, TLRs, and NOD2, interacting directly with the LUBAC E3 ligase complex to modulate linear ubiquitin signaling and NF-κB pathway activity. Deficiency or dysfunction in OTULIN leads to severe innate immune disturbances, systemic autoinflammation, and developmental defects. OTULIN is therefore a promising (although challenging) therapeutic target for immune, autoimmune, and inflammatory diseases, as well as broader cell fate regulation.

Other names

Family with sequence similarity 105, member B (FAM105B)GumbyDeubiquitinating enzyme otulinOTU domain-containing deubiquitinase with linear linkage specificityUbiquitin thioesterase GumbyOTU deubiquitinase with linear linkage specificityAIPDSIMD107FLJ34884

Inhibition: Would prevent OTULIN from hydrolyzing Met1-linked polyubiquitin, potentially enhancing pro-inflammatory or apoptotic signals. Activation: Would enhance deubiquitination, reducing inflammation or suppressing inappropriate cell death. Drugs would modulate the balance of linear ubiquitin signaling in immune and apoptotic pathways.