RPN1, also known as ribophorin I, is a type I transmembrane protein that is part of an N-oligosaccharyl-transferase complex and plays a vital role in glycosylation [4,5]. It is involved in multiple biological processes such as the regulation of the 26S proteasome assembly and function through reversible phosphorylation of Ser361 in Rpn1 [7]. It is also implicated in ER-phagy, where the UFL1 ligase brought by DDRGK1 to the ER surface UFMylates RPN1 as part of the process to repress the unfolded protein response via IRE1α [3].

In cancer research, deletion of the RPN1 gene imparts resistance to disulfidptosis, a newly identified cell death modality, and RPN1 primarily induces cell skeleton breakdown to facilitate disulfidptosis under glucose-starved conditions in breast and lung cancer cell lines [1]. RPN1 is aberrantly expressed in triple-negative breast cancer (TNBC) cells, correlating with increased proliferation and poor prognosis. Its deletion improves the TNBC microenvironment and enhances the efficacy of anti-PD-1 therapy as it mediates post-translational modification of PD-L1, enhancing its glycosylation and stability [4]. In breast cancer cells, knockdown of RPN1 induces apoptosis and attenuates proliferation, migration, and invasion by down-regulating the PI3K/AKT/mTOR signaling pathway [5]. In hepatocellular carcinoma, circ-SNX27 accelerates progression by modulating the miR-375/RPN1 axis [2]. Pan-cancer analysis shows RPN1 is aberrantly expressed in various cancers, affects patient prognosis, is associated with immune cell infiltration, tumor mutation burden, microsatellite instability, and drug sensitivity, and has diagnostic potential in glioma [6].

In conclusion, RPN1 has diverse functions in biological processes, with its role in glycosylation being fundamental. In disease, especially in cancers, RPN1 is closely associated with tumor cell proliferation, invasion, apoptosis, immune evasion, and response to immunotherapy. Studies using gene-knockdown or deletion models in cell lines have been crucial in revealing these functions, providing potential targets for cancer treatment.

References:

1. Wang, Xing, Zhu, Hong-Quan, Lin, Shi-Ming, Xia, Bao-Ying, Xu, Bo. 2024. RPN1: a pan-cancer biomarker and disulfidptosis regulator. In Translational cancer research, 13, 2518-2534. doi:10.21037/tcr-24-581. https://pubmed.ncbi.nlm.nih.gov/38881923/

2. Zheng, Chao, Liang, Jin, Yu, Shoude, Dai, Lin, Xu, Dan. . Circ-SNX27 sponging miR-375/RPN1 axis contributes to hepatocellular carcinoma progression. In The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology, 27, 333-344. doi:10.4196/kjpp.2023.27.4.333. https://pubmed.ncbi.nlm.nih.gov/37386831/

3. Liang, Jin Rui, Lingeman, Emily, Luong, Thao, Olzmann, James A, Corn, Jacob E. 2020. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation. In Cell, 180, 1160-1177.e20. doi:10.1016/j.cell.2020.02.017. https://pubmed.ncbi.nlm.nih.gov/32160526/

4. Wang, Mengxue, Li, Xunjia, Wu, Yushen, Li, Shengwei, Yin, Xuedong. 2025. Loss of RPN1 promotes antitumor immunity via PD-L1 checkpoint blockade in triple-negative breast cancer - experimental studies. In International journal of surgery (London, England), 111, 1801-1813. doi:10.1097/JS9.0000000000002164. https://pubmed.ncbi.nlm.nih.gov/39705151/

5. Shen, Wei-Juan, Zhang, Yi. 2024. RPN1 promotes the proliferation and invasion of breast cancer cells by activating the PI3K/AKT/mTOR signaling pathway. In Discover oncology, 15, 25. doi:10.1007/s12672-024-00875-8. https://pubmed.ncbi.nlm.nih.gov/38302629/

6. Zong, Yan, Zhu, Ankang, Liu, Peipei, Chen, Shuai, Gao, Xingcai. 2024. Pan-cancer analysis of the disulfidptosis-related gene RPN1 and its potential biological function and prognostic significance in gliomas. In Heliyon, 10, e31875. doi:10.1016/j.heliyon.2024.e31875. https://pubmed.ncbi.nlm.nih.gov/38845861/

7. Liu, Xiaoyan, Xiao, Weidi, Zhang, Yanan, Xu, Ping, Guo, Xing. 2019. Reversible phosphorylation of Rpn1 regulates 26S proteasome assembly and function. In Proceedings of the National Academy of Sciences of the United States of America, 117, 328-336. doi:10.1073/pnas.1912531117. https://pubmed.ncbi.nlm.nih.gov/31843888/