RRBP1, also known as ribosome-binding protein 1, is a ribosome-binding transmembrane protein of the endoplasmic reticulum (ER). It plays crucial roles in multiple biological processes. In neurons, it is involved in axonal local translation, where it serves as a ribosome receptor to regulate this process and is associated with axon morphology development [1]. In cells, it is also implicated in the mitophagy pathway, responding to mitochondrial protein import stress through interaction with NLRX1 to control LC3 lipidation [2,8].

In cancer research, RRBP1 has been shown to be highly expressed in various cancers. In upper tract urothelial carcinoma (UTUC), its gene body hypomethylation is associated with high expression, potentiating tumor malignancy and chemoresistance [3]. In oral squamous cell carcinoma, it regulates the Hippo pathway to induce cisplatin-resistance, and its inhibition can reverse this resistance [4]. In bladder cancer, high RRBP1 expression is related to tumor stage, lymph node metastasis, and prognosis, and knockdown inhibits cell migration and invasion [5]. In epithelial ovarian cancer, its high expression is associated with poor prognosis and is an independent predictor of overall and disease-free survival [9]. In prostate cancer, high RRBP1 expression is related to T stage, lymph node metastasis, and prognosis, and can serve as an independent prognostic factor [10]. Also, in prostate cancer, METTL3 stabilizes RRBP1 mRNA in an m6A-dependent manner, and targeting this axis can be a therapeutic strategy [7]. In bone metastatic cancer cells, depletion of RRBP1 enhances the osteoblastic phenotype expression, suggesting its role in the bone microenvironment [6].

In conclusion, RRBP1 is a multifunctional protein. Its roles in axonal translation and mitophagy highlight its importance in normal cellular function. In cancer, its consistent over-expression and association with poor prognosis and chemoresistance in multiple cancer types suggest that it could be a potential therapeutic target. The studies on RRBP1 using various models, though not specifically KO/CKO mouse models in all cases, have provided valuable insights into its functions in different biological and disease contexts.

References:

1. Koppers, Max, Özkan, Nazmiye, Nguyen, Ha H, Hoogenraad, Casper C, Farías, Ginny G. 2024. Axonal endoplasmic reticulum tubules control local translation via P180/RRBP1-mediated ribosome interactions. In Developmental cell, 59, 2053-2068.e9. doi:10.1016/j.devcel.2024.05.005. https://pubmed.ncbi.nlm.nih.gov/38815583/

2. Killackey, Samuel A, Bi, Yuntian, Soares, Fraser, Arnoult, Damien, Girardin, Stephen E. 2022. Mitochondrial protein import stress regulates the LC3 lipidation step of mitophagy through NLRX1 and RRBP1. In Molecular cell, 82, 2815-2831.e5. doi:10.1016/j.molcel.2022.06.004. https://pubmed.ncbi.nlm.nih.gov/35752171/

3. Luo, Hao-Lun, Liu, Hui-Ying, Chang, Yin-Lun, Huang, Chun-Chieh, Peng, Jei-Ming. 2021. Hypomethylated RRBP1 Potentiates Tumor Malignancy and Chemoresistance in Upper Tract Urothelial Carcinoma. In International journal of molecular sciences, 22, . doi:10.3390/ijms22168761. https://pubmed.ncbi.nlm.nih.gov/34445467/

4. Shriwas, Omprakash, Arya, Rakesh, Mohanty, Sibasish, Nanda, Ranjan K, Dash, Rupesh. 2021. RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway. In British journal of cancer, 124, 2004-2016. doi:10.1038/s41416-021-01336-7. https://pubmed.ncbi.nlm.nih.gov/33762722/

5. Wang, Mingshuai, Liu, Sai, Zhou, Bolin, Ping, Hao, Xing, Nianzeng. 2020. RRBP1 is highly expressed in bladder cancer and is associated with migration and invasion. In Oncology letters, 20, 203. doi:10.3892/ol.2020.12066. https://pubmed.ncbi.nlm.nih.gov/32963609/

6. Chen, Rui, Wang, Yue, Xu, Yang, Xia, Chun, Zhang, Bing. 2022. RRBP1 depletion of bone metastatic cancer cells contributes to enhanced expression of the osteoblastic phenotype. In Frontiers in oncology, 12, 1005152. doi:10.3389/fonc.2022.1005152. https://pubmed.ncbi.nlm.nih.gov/36568157/

7. Feng, Yuqing, Li, Zenghui, Zhu, Jinwei, Shi, Junfeng, Zhang, Dingxiao. 2024. Stabilization of RRBP1 mRNA via an m6A-dependent manner in prostate cancer constitutes a therapeutic vulnerability amenable to small-peptide inhibition of METTL3. In Cellular and molecular life sciences : CMLS, 81, 414. doi:10.1007/s00018-024-05418-6. https://pubmed.ncbi.nlm.nih.gov/39367907/

8. Killackey, Samuel A, Bi, Yuntian, Philpott, Dana J, Arnoult, Damien, Girardin, Stephen E. 2022. Mitochondria-ER cooperation: NLRX1 detects mitochondrial protein import stress and promotes mitophagy through the ER protein RRBP1. In Autophagy, 19, 1601-1603. doi:10.1080/15548627.2022.2129763. https://pubmed.ncbi.nlm.nih.gov/36170592/

9. Ma, Jing, Ren, Sujing, Ding, Jing, Ma, Rong, Meng, Fanling. 2019. Expression of RRBP1 in epithelial ovarian cancer and its clinical significance. In Bioscience reports, 39, . doi:10.1042/BSR20190656. https://pubmed.ncbi.nlm.nih.gov/31285390/

10. Li, Tieqiu, Wang, Qianqian, Hong, Xiuqin, Li, Jiahui, Lei, Bin. 2019. RRBP1 is highly expressed in prostate cancer and correlates with prognosis. In Cancer management and research, 11, 3021-3027. doi:10.2147/CMAR.S186632. https://pubmed.ncbi.nlm.nih.gov/31118771/