Rtp4, or receptor transporter protein 4, is an interferon-stimulated gene and a chaperon protein of G protein-coupled receptors. It plays significant roles in multiple biological processes, especially in the body's response to viral infections and in cancer-related events. It has been associated with immune-related pathways and its function is crucial for understanding host-virus interactions and tumor-immune regulation [2,3].

In terms of viral infections, over-expression of Rtp4 reduces the viral titer of Rabies lyssavirus (RABV) in neuronal cells. Rtp4 binds to the viral genomic RNA (vRNA) of RABV, suppressing the whole viral genome amplification. The zinc finger domain (ZFD) of Rtp4 exerts this antiviral function, with an important amino acids site (C95) in the 3CxxC motif being essential [1]. In herpes simplex virus (HSV)-1 infection, elevated Rtp4 in the corneal epithelium of type 2 diabetes mellitus (T2D) mice exacerbates HSV-1 infection by enhancing its binding to corneal epithelial cells, while Rtp4 knockdown mitigates corneal lesions [6]. Rtp4 also restricts the replication of flaviviruses like Zika, West Nile, and hepatitis C viruses, as well as the human coronavirus HCoV-OC43 and SARS-CoV-2, by binding to viral RNA and suppressing viral genome amplification [8,9]. In malaria parasite infection, Rtp4-/-mice showed a significantly higher level of IFN-I response in microglia, lower parasitemia, fewer neurologic symptoms, and better survival rates, indicating that Rtp4 negatively regulates the TBK1 signaling pathway during infection [7].

In cancer-related studies, Rtp4 silencing in colorectal cancer cells provokes tumor-intrinsic resistance to immune checkpoint blockade (ICB). Anti-PD-1 antibody fails to recruit T lymphocytes in Rtp4-KO MC38 cells [2]. Rtp4 is also identified as a novel prognosis-related hub gene in cutaneous melanoma, associated with immune cell infiltration and genes encoding components of immune checkpoints (PDCD1, TIM-3, and LAG3) [4]. In addition, Rtp4 might be a potential biomarker for diagnosing pulmonary tuberculosis, with its expression significantly upregulated in the pulmonary tuberculosis group compared to the healthy control group in some gene sets, and downregulated after antituberculosis therapy [5]. Overall, Rtp4 is involved in both antiviral defense mechanisms and cancer-related immune regulation. Gene knockout models, especially in mice, have been instrumental in revealing its functions in these disease-related processes, providing potential targets for therapy in viral diseases, cancer, and tuberculosis.

References:

1. Sui, Baokun, Zheng, Jiaxin, Zhao, Juanjuan, Zhou, Ming, Zhao, Ling. 2024. RTP4 restricts lyssavirus rabies infection by binding to viral genomic RNA. In Veterinary microbiology, 295, 110159. doi:10.1016/j.vetmic.2024.110159. https://pubmed.ncbi.nlm.nih.gov/38941768/

2. Yamamoto, Yudai, Shimada, Shu, Akiyama, Yoshimitsu, Kawakami, Yutaka, Tanaka, Shinji. 2023. RTP4 silencing provokes tumor-intrinsic resistance to immune checkpoint blockade in colorectal cancer. In Journal of gastroenterology, 58, 540-553. doi:10.1007/s00535-023-01969-w. https://pubmed.ncbi.nlm.nih.gov/36859628/

3. Wroblewska, Aleksandra, Dhainaut, Maxime, Ben-Zvi, Benjamin, Rahman, Adeeb H, Brown, Brian D. 2018. Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens. In Cell, 175, 1141-1155.e16. doi:10.1016/j.cell.2018.09.022. https://pubmed.ncbi.nlm.nih.gov/30343902/

4. Li, Yiqi, Qi, Jue, Yang, Jiankang. 2021. RTP4 is a novel prognosis-related hub gene in cutaneous melanoma. In Hereditas, 158, 22. doi:10.1186/s41065-021-00183-z. https://pubmed.ncbi.nlm.nih.gov/34154655/

5. Li, Hao, Zhou, Qin, Ding, ZhiXiang, Wang, QingHai. 2023. RTP4, a Biomarker Associated with Diagnosing Pulmonary Tuberculosis and Pan-Cancer Analysis. In Mediators of inflammation, 2023, 2318473. doi:10.1155/2023/2318473. https://pubmed.ncbi.nlm.nih.gov/37152371/

6. Dai, Yunhai, Mao, Shilan, Zang, Xinyi, Zhou, Qingjun, Wang, Xiaolei. . RTP4 Enhances Corneal HSV-1 Infection in Mice With Type 2 Diabetes Mellitus. In Investigative ophthalmology & visual science, 65, 36. doi:10.1167/iovs.65.11.36. https://pubmed.ncbi.nlm.nih.gov/39312222/

7. He, Xiao, Ashbrook, Alison W, Du, Yang, Rice, Charles M, Su, Xin-Zhuan. 2020. RTP4 inhibits IFN-I response and enhances experimental cerebral malaria and neuropathology. In Proceedings of the National Academy of Sciences of the United States of America, 117, 19465-19474. doi:10.1073/pnas.2006492117. https://pubmed.ncbi.nlm.nih.gov/32709745/

8. Boys, Ian N, Xu, Elaine, Mar, Katrina B, Moon, Benjamin, Schoggins, John W. 2020. RTP4 Is a Potent IFN-Inducible Anti-flavivirus Effector Engaged in a Host-Virus Arms Race in Bats and Other Mammals. In Cell host & microbe, 28, 712-723.e9. doi:10.1016/j.chom.2020.09.014. https://pubmed.ncbi.nlm.nih.gov/33113352/

9. Kaur, Ramanjit, Tada, Takuya, Landau, Nathaniel Roy. 2023. Restriction of SARS-CoV-2 replication by receptor transporter protein 4 (RTP4). In mBio, 14, e0109023. doi:10.1128/mbio.01090-23. https://pubmed.ncbi.nlm.nih.gov/37382452/