Gpr108, a member of the G protein-coupled receptor superfamily, has diverse functions. It is involved in multiple biological processes such as antiviral innate immunity, NF-κB signaling regulation, and serves as an entry factor for adeno-associated virus (AAV) [1,2,3]. In the immune system, it can interact with various signaling components related to Toll-like receptor (TLR)-mediated signaling pathways [4].

Depletion of Gpr108 in various cancer cells dramatically inhibits their survival [1]. Gpr108 knockout totally impairs TNFα activation of NF-κB, and knockout also blocks the ability of gambogic acid to inhibit NF-κB signaling, indicating its crucial role in this anti-cancer mechanism [1]. In antiviral immunity, Golgi-resident Gpr108 cooperates with E3 ubiquitin ligase Smurf1 to suppress type Ι interferon responses by promoting the autophagic degradation of phosphorylated IRF3 [2]. In AAV-related studies, Gpr108 knockout in mice shows 10-to 100-fold reduced expression for AAV8 and rh32.33 but not AAV5, suggesting its importance as an AAV entry factor with serotype selectivity [3].

In summary, Gpr108 is essential in regulating immune-related signaling pathways and AAV transduction. Gene knockout models, especially in mice, have revealed its significance in cancer, antiviral immune responses, and AAV-mediated gene therapy, providing potential therapeutic targets and insights into disease mechanisms [1,2,3].

References:

1. Lyu, Song, Zhang, Xue, Tu, Zhenzhen, Ke, Xisong, Qu, Yi. 2022. GPR108 is required for gambogic acid inhibiting NF-κB signaling in cancer. In Pharmacological research, 182, 106279. doi:10.1016/j.phrs.2022.106279. https://pubmed.ncbi.nlm.nih.gov/35659621/

2. Zhao, Mengyuan, Zhang, Yong, Qiang, Lihua, Zhang, Lingqiang, Liu, Cui Hua. 2023. A Golgi-resident GPR108 cooperates with E3 ubiquitin ligase Smurf1 to suppress antiviral innate immunity. In Cell reports, 42, 112655. doi:10.1016/j.celrep.2023.112655. https://pubmed.ncbi.nlm.nih.gov/37330913/

3. Dudek, Amanda M, Zabaleta, Nerea, Zinn, Eric, Zhou, Guo Ling, Vandenberghe, Luk H. 2019. GPR108 Is a Highly Conserved AAV Entry Factor. In Molecular therapy : the journal of the American Society of Gene Therapy, 28, 367-381. doi:10.1016/j.ymthe.2019.11.005. https://pubmed.ncbi.nlm.nih.gov/31784416/

4. Dong, Danfeng, Zhou, Haisheng, Na, Soon-Young, Seed, Brian, Zhou, Guo Ling. 2018. GPR108, an NF-κB activator suppressed by TIRAP, negatively regulates TLR-triggered immune responses. In PloS one, 13, e0205303. doi:10.1371/journal.pone.0205303. https://pubmed.ncbi.nlm.nih.gov/30332431/