USP27X, a deubiquitylase, plays crucial roles in multiple biological processes. It is involved in cell proliferation, neural development, and various signaling pathways, such as antiviral, immune, and cancer-related pathways. Its functions are vital for maintaining normal cellular homeostasis, and understanding its role can offer insights into disease mechanisms [1,3,4,5,6,7,8,9].

In X-linked intellectual disability disorder 105 (XLID105), hemizygous variants in USP27X disrupt protein function, highlighting its importance in neural development [1]. In breast cancer, USP27X is required for cell proliferation and tumorigenesis. PIM2 phosphorylates USP27X, promoting MYC deubiquitylation, protein stability, and aerobic glycolysis. Additionally, in another breast cancer-related study, GSK3β phosphorylates USP27X, enhancing the stability and oncogenic functions of CBX2 [4,5]. In hepatocellular carcinoma, the lncRNA USP27X-AS1 promotes cancer progression [2]. In antiviral responses, USP27X negatively regulates RIG-I-mediated antiviral signaling by deubiquitinating RIG-I [3]. In EMT and fibroblast activation, USP27X increases Snail1 stability, regulating cell migration and chemoresistance [7]. It also deubiquitinates and stabilizes the DNA sensor cGAS to regulate cytosolic DNA-mediated signaling, and can affect apoptosis by regulating proteins like cFLIPL and Bim [6,8,9].

In conclusion, USP27X is a key deubiquitylase involved in a wide range of biological processes and diseases, including neural development-related intellectual disability and multiple types of cancer. Understanding its functions through studies, such as those on gene variants in XLID105 and its roles in cancer-associated signaling pathways, can potentially lead to the development of targeted therapies for these diseases.

References:

1. Koch, Intisar, Slovik, Maya, Zhang, Yuling, Bustos, Francisco, Harel, Tamar. 2024. USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms. In Life science alliance, 7, . doi:10.26508/lsa.202302258. https://pubmed.ncbi.nlm.nih.gov/38182161/

2. Su, Chen, Zhang, Haoquan, Mo, Jie, Zhang, Bixiang, Zhu, Peng. . SP1-activated USP27X-AS1 promotes hepatocellular carcinoma progression via USP7-mediated AKT stabilisation. In Clinical and translational medicine, 14, e1563. doi:10.1002/ctm2.1563. https://pubmed.ncbi.nlm.nih.gov/38279869/

3. Tao, Xinyue, Chu, Bei, Xin, Di, Li, Lin, Sun, Qinmiao. 2020. USP27X negatively regulates antiviral signaling by deubiquitinating RIG-I. In PLoS pathogens, 16, e1008293. doi:10.1371/journal.ppat.1008293. https://pubmed.ncbi.nlm.nih.gov/32027733/

4. Han, Xue, Ren, Chune, Lu, Chao, Liu, Lan, Yu, Zhenhai. 2024. Phosphorylation of USP27X by PIM2 promotes glycolysis and breast cancer progression via deubiquitylation of MYC. In Oncogene, 43, 2493-2503. doi:10.1038/s41388-024-03097-y. https://pubmed.ncbi.nlm.nih.gov/38969771/

5. Xing, Yushu, Ba-Tu, Jirimu, Dong, Chongyang, Wang, Huanyun, Wang, Minjie. 2023. Phosphorylation of USP27X by GSK3β maintains the stability and oncogenic functions of CBX2. In Cell death & disease, 14, 782. doi:10.1038/s41419-023-06304-y. https://pubmed.ncbi.nlm.nih.gov/38030604/

6. Dold, Manuel Nico, Ng, Xiulin, Alber, Claudia, Häcker, Georg, Weber, Arnim. 2022. The deubiquitinase Usp27x as a novel regulator of cFLIPL protein expression and sensitizer to death-receptor-induced apoptosis. In Apoptosis : an international journal on programmed cell death, 27, 112-132. doi:10.1007/s10495-021-01706-9. https://pubmed.ncbi.nlm.nih.gov/35044632/

7. Lambies, Guillem, Miceli, Martina, Martínez-Guillamon, Catalina, García de Herreros, Antonio, Díaz, Víctor M. 2018. TGFβ-Activated USP27X Deubiquitinase Regulates Cell Migration and Chemoresistance via Stabilization of Snail1. In Cancer research, 79, 33-46. doi:10.1158/0008-5472.CAN-18-0753. https://pubmed.ncbi.nlm.nih.gov/30341066/

8. Guo, Yunyun, Jiang, Fei, Kong, Lingli, Zheng, Yi, Gao, Chengjiang. 2019. Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling. In Journal of immunology (Baltimore, Md. : 1950), 203, 2049-2054. doi:10.4049/jimmunol.1900514. https://pubmed.ncbi.nlm.nih.gov/31534008/

9. Weber, Arnim, Heinlein, Melanie, Dengjel, Jörn, Singh, Prafull Kumar, Häcker, Georg. 2016. The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis. In EMBO reports, 17, 724-38. doi:10.15252/embr.201541392. https://pubmed.ncbi.nlm.nih.gov/27013495/