Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation
As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clini...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-07-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.835603/full |
| _version_ | 1828374241158889472 |
|---|---|
| author | Meng Wei Meng Wei Yunhai Mo Yunhai Mo Jialong Liu Jingtong Zhai Huilong Li Huilong Li Yixin Xu Yixin Xu Yumeng Peng Yumeng Peng Zhihong Tang Zhihong Tang Tao Wei Tao Wei Xiaopan Yang Linfei Huang Xiao Shao Jingfei Li Li Zhou Hui Zhong Congwen Wei Qiaosheng Xie Min Min Feixiang Wu Feixiang Wu |
| author_facet | Meng Wei Meng Wei Yunhai Mo Yunhai Mo Jialong Liu Jingtong Zhai Huilong Li Huilong Li Yixin Xu Yixin Xu Yumeng Peng Yumeng Peng Zhihong Tang Zhihong Tang Tao Wei Tao Wei Xiaopan Yang Linfei Huang Xiao Shao Jingfei Li Li Zhou Hui Zhong Congwen Wei Qiaosheng Xie Min Min Feixiang Wu Feixiang Wu |
| author_sort | Meng Wei |
| collection | DOAJ |
| description | As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy. |
| first_indexed | 2024-04-14T07:30:01Z |
| format | Article |
| id | doaj.art-48ae264efab242bbb6893345aab19443 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T07:30:01Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-48ae264efab242bbb6893345aab194432022-12-22T02:05:53ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.835603835603Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradationMeng Wei0Meng Wei1Yunhai Mo2Yunhai Mo3Jialong Liu4Jingtong Zhai5Huilong Li6Huilong Li7Yixin Xu8Yixin Xu9Yumeng Peng10Yumeng Peng11Zhihong Tang12Zhihong Tang13Tao Wei14Tao Wei15Xiaopan Yang16Linfei Huang17Xiao Shao18Jingfei Li19Li Zhou20Hui Zhong21Congwen Wei22Qiaosheng Xie23Min Min24Feixiang Wu25Feixiang Wu26Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaDepartment of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Medical Oncology and State Key Laboratory of Molecular Oncology, National Cancer Center/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaDepartment of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaDepartment of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaDepartment of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaDepartment of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Gastroenterology, First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, ChinaDepartment of Radiation Oncology, China-Japan Friendship Hospital, Beijing, ChinaDepartment of Gastroenterology, First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, ChinaDepartment of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, ChinaKey Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education, Nanning, ChinaAs a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy.https://www.frontiersin.org/articles/10.3389/fonc.2022.835603/fullRNF125PD-L1ubiquitinationtumor immunotherapyclinical outcome |
| spellingShingle | Meng Wei Meng Wei Yunhai Mo Yunhai Mo Jialong Liu Jingtong Zhai Huilong Li Huilong Li Yixin Xu Yixin Xu Yumeng Peng Yumeng Peng Zhihong Tang Zhihong Tang Tao Wei Tao Wei Xiaopan Yang Linfei Huang Xiao Shao Jingfei Li Li Zhou Hui Zhong Congwen Wei Qiaosheng Xie Min Min Feixiang Wu Feixiang Wu Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation Frontiers in Oncology RNF125 PD-L1 ubiquitination tumor immunotherapy clinical outcome |
| title | Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation |
| title_full | Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation |
| title_fullStr | Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation |
| title_full_unstemmed | Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation |
| title_short | Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation |
| title_sort | ubiquitin ligase rnf125 targets pd l1 for ubiquitination and degradation |
| topic | RNF125 PD-L1 ubiquitination tumor immunotherapy clinical outcome |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.835603/full |
| work_keys_str_mv | AT mengwei ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT mengwei ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT yunhaimo ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT yunhaimo ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT jialongliu ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT jingtongzhai ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT huilongli ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT huilongli ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT yixinxu ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT yixinxu ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT yumengpeng ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT yumengpeng ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT zhihongtang ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT zhihongtang ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT taowei ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT taowei ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT xiaopanyang ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT linfeihuang ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT xiaoshao ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT jingfeili ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT lizhou ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT huizhong ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT congwenwei ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT qiaoshengxie ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT minmin ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT feixiangwu ubiquitinligasernf125targetspdl1forubiquitinationanddegradation AT feixiangwu ubiquitinligasernf125targetspdl1forubiquitinationanddegradation |