OTU domain-containing protein 4 (OTUD4)

OTU domain-containing protein 4 (OTUD4) is a cytoplasmic deubiquitinating enzyme belonging to the OTU protease family. It specifically cleaves K48-linked ubiquitin chains on proteins, stabilizing substrates involved in DNA repair, translation, and stress responses. OTUD4 forms part of neuronal RNA transport granules and is recruited to stress granules under cellular stress, where it regulates granule formation and local protein synthesis. Its depletion results in defective stress granule formation and increased apoptosis. OTUD4 plays crucial roles in regulating translation, TGFβ signaling, and cell proliferation. Mutations and altered expression of OTUD4 are linked to neurodegenerative diseases such as ALS and dementia, rare genetic disorders (Gordon Holmes syndrome), and several cancers including glioblastoma, where it promotes tumor progression through stabilization of CDK1 and enhancement of MAPK pathway signaling. OTUD4 primarily acts as a scaffold for other DUBs, such as USP7 and USP9X, to regulate DNA alkylation damage repair proteins such as ALKBH2/ALKBH3, with its catalytic activity sometimes dispensable for function.

Other names

OTUD4HIN-1KIAA1046HSHIN1DUBA6HIV-1-induced protein HIN-1HIN1

Drugs targeting OTUD4 would be expected to inhibit its deubiquitinase activity, destabilize key substrates, and sensitize cells to stress or DNA alkylating agents