Ovarian tumor domain-containing protein 4 (OTUD4) (OTUD4)

Ovarian tumor domain-containing protein 4 (OTUD4) is a member of the ovarian tumor (OTU) family of deubiquitinating enzymes (DUBs) that plays a pivotal role in regulating protein stability and cellular signaling. It is uniquely characterized by its ability to switch between K48- and K63-linked deubiquitinase activities depending on its phosphorylation state, allowing it to modulate diverse processes such as DNA repair and innate immunity (Zhao et al., 2018). OTUD4 acts as a critical negative regulator of the inflammatory response by deubiquitinating the adapter protein MyD88, thereby suppressing Toll-like receptor (TLR)-mediated NF-kappaB activation and the subsequent production of pro-inflammatory cytokines and chemokines (Zhao et al., 2018; Liuyu et al., 2019). In oncology, OTUD4 has been identified as a driver of immune evasion, particularly in triple-negative breast cancer, where it stabilizes the immunosuppressive molecule CD73 by counteracting its ubiquitination (Pharmacological suppression of the OTUD4/CD73 proteolytic axis, 2024). Experimental small molecule inhibitors like ST80 have shown promise in disrupting the OTUD4-CD73 axis to revive anti-tumor immunity (Pharmacological suppression of the OTUD4/CD73 proteolytic axis, 2024). Beyond cancer and inflammation, OTUD4 is involved in the repair of DNA alkylation damage and the regulation of RNA granules, making it a multifaceted therapeutic target (Das et al., 2019).

Other names

OTU domain-containing protein 4HIN-1HIV-1-induced protein HIN-1HIN1Deubiquitinating enzyme OTUD4

Inhibition of OTUD4-mediated deubiquitination to destabilize pro-tumorigenic substrates (e.g., CD73) or to modulate inflammatory signaling pathways such as the MyD88/NF-kappaB axis.