Usp18, also known as UBP43, is a special member of the ubiquitin-specific proteases (USPs) family. As a deubiquitinase (DUB), it specifically removes the ubiquitin-like protein ISG15 from target proteins, reversing the ISGylation process. It is also a major negative regulator of the type I interferon response, playing a crucial role in immune-related pathways and overall biological balance. Genetic models, such as knockout (KO) mouse models, have been essential for studying its functions [2,3,4].

In KO mouse models, deficiency of Usp18 makes mice more susceptible to RNA virus infection, indicating its role in innate antiviral immunity. It promotes K63-linked polyubiquitination and aggregation of MAVS, a key adaptor molecule in Rig-I-like receptor (RLR) signaling, upregulating the expression and production of type I interferon [1]. In the context of cancer, engineered loss of Usp18 increases ISGylation, reduces cancer cell growth by triggering apoptosis, and represses cancer formation in engineered murine lung cancer models, suggesting its potential as an antineoplastic target [5].

In summary, Usp18 is multifunctional, playing important roles in innate antiviral immunity and cancer development. Studies using KO mouse models have revealed its significance in these biological processes and disease conditions, providing valuable insights into potential therapeutic strategies for infectious diseases and cancer.

References:

1. Hou, Jinxiu, Han, Lulu, Zhao, Ze, Zheng, Yi, Gao, Chengjiang. 2021. USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS. In Nature communications, 12, 2970. doi:10.1038/s41467-021-23219-4. https://pubmed.ncbi.nlm.nih.gov/34016972/

2. Basters, Anja, Knobeloch, Klaus-Peter, Fritz, Günter. 2018. USP18 - a multifunctional component in the interferon response. In Bioscience reports, 38, . doi:10.1042/BSR20180250. https://pubmed.ncbi.nlm.nih.gov/30126853/

3. Kang, Ji An, Jeon, Young Joo. 2020. Emerging Roles of USP18: From Biology to Pathophysiology. In International journal of molecular sciences, 21, . doi:10.3390/ijms21186825. https://pubmed.ncbi.nlm.nih.gov/32957626/

4. Jiménez Fernández, Daniel, Hess, Sandra, Knobeloch, Klaus-Peter. 2020. Strategies to Target ISG15 and USP18 Toward Therapeutic Applications. In Frontiers in chemistry, 7, 923. doi:10.3389/fchem.2019.00923. https://pubmed.ncbi.nlm.nih.gov/32039148/

5. Mustachio, Lisa Maria, Lu, Yun, Kawakami, Masanori, Liu, Xi, Dmitrovsky, Ethan. 2018. Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target. In Cancer research, 78, 587-592. doi:10.1158/0008-5472.CAN-17-1752. https://pubmed.ncbi.nlm.nih.gov/29343520/