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PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination
Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers coinhibi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888393/ https://www.ncbi.nlm.nih.gov/pubmed/36719382 http://dx.doi.org/10.1172/JCI160456 |
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author | Yu, Xinfang Li, Wei Liu, Haidan Wang, Xu Coarfa, Cristian Cheng, Chao Yu, Xinlian Zeng, Zhaoyang Cao, Ya Young, Ken H. Li, Yong |
author_facet | Yu, Xinfang Li, Wei Liu, Haidan Wang, Xu Coarfa, Cristian Cheng, Chao Yu, Xinlian Zeng, Zhaoyang Cao, Ya Young, Ken H. Li, Yong |
author_sort | Yu, Xinfang |
collection | PubMed |
description | Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers coinhibitory signals to T cells, thereby suppressing their function and allowing evasion of antitumor immunity. Most companion or complementary diagnostic devices for assessing PD-L1 expression levels in tumor cells used in the clinic or in clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, we showed that mind bomb homolog 2 (MIB2) is required for PD-L1 transportation from the trans-Golgi network (TGN) to the plasma membrane of cancer cells. MIB2 deficiency led to fewer PD-L1 proteins on the tumor cell surface and promoted antitumor immunity in mice. Mechanistically, MIB2 catalyzed nonproteolytic K63-linked ubiquitination of PD-L1, facilitating PD-L1 trafficking through Ras-associated binding 8–mediated (RAB8-mediated) exocytosis from the TGN to the plasma membrane, where it bound PD-1 extrinsically to prevent tumor cell killing by T cells. Our findings demonstrate that nonproteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cell immune evasion. |
format | Online Article Text |
id | pubmed-9888393 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-98883932023-02-06 PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination Yu, Xinfang Li, Wei Liu, Haidan Wang, Xu Coarfa, Cristian Cheng, Chao Yu, Xinlian Zeng, Zhaoyang Cao, Ya Young, Ken H. Li, Yong J Clin Invest Research Article Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers coinhibitory signals to T cells, thereby suppressing their function and allowing evasion of antitumor immunity. Most companion or complementary diagnostic devices for assessing PD-L1 expression levels in tumor cells used in the clinic or in clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, we showed that mind bomb homolog 2 (MIB2) is required for PD-L1 transportation from the trans-Golgi network (TGN) to the plasma membrane of cancer cells. MIB2 deficiency led to fewer PD-L1 proteins on the tumor cell surface and promoted antitumor immunity in mice. Mechanistically, MIB2 catalyzed nonproteolytic K63-linked ubiquitination of PD-L1, facilitating PD-L1 trafficking through Ras-associated binding 8–mediated (RAB8-mediated) exocytosis from the TGN to the plasma membrane, where it bound PD-1 extrinsically to prevent tumor cell killing by T cells. Our findings demonstrate that nonproteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cell immune evasion. American Society for Clinical Investigation 2023-02-01 /pmc/articles/PMC9888393/ /pubmed/36719382 http://dx.doi.org/10.1172/JCI160456 Text en © 2023 Yu et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Yu, Xinfang Li, Wei Liu, Haidan Wang, Xu Coarfa, Cristian Cheng, Chao Yu, Xinlian Zeng, Zhaoyang Cao, Ya Young, Ken H. Li, Yong PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination |
title | PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination |
title_full | PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination |
title_fullStr | PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination |
title_full_unstemmed | PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination |
title_short | PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination |
title_sort | pd-l1 translocation to the plasma membrane enables tumor immune evasion through mib2 ubiquitination |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888393/ https://www.ncbi.nlm.nih.gov/pubmed/36719382 http://dx.doi.org/10.1172/JCI160456 |
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