PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner
Abstract Small extracellular vesicles (sEVs), carrying PD-L1, have been implicated in immune evasion and tumor progression. However, understanding how PD-L1 sEVs are secreted still needs to be improved. We found that the secretion dynamics of PD-L1 sEVs is similar to that of other sEVs. Intracellula...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07341-5 |
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| author | Ren Zhang Weilin Liao Xi Chen Junyi Wang Jiaqi Li Geer Chen Weiyu Wu Xiaoxuan Wang Yao Zhang Ziyu Chen Xiaoyu Zhu Zicong Lin Yizhun Zhu Lijuan Ma Haijie Yu |
| author_facet | Ren Zhang Weilin Liao Xi Chen Junyi Wang Jiaqi Li Geer Chen Weiyu Wu Xiaoxuan Wang Yao Zhang Ziyu Chen Xiaoyu Zhu Zicong Lin Yizhun Zhu Lijuan Ma Haijie Yu |
| author_sort | Ren Zhang |
| collection | DOAJ |
| description | Abstract Small extracellular vesicles (sEVs), carrying PD-L1, have been implicated in immune evasion and tumor progression. However, understanding how PD-L1 sEVs are secreted still needs to be improved. We found that the secretion dynamics of PD-L1 sEVs is similar to that of other sEVs. Intracellular calcium and the associated downstream PKC signaling plays pivotal roles in releasing PD-L1 sEVs in non-small cell lung cancer cells (NSCLC). Particularly, we observed that knocking down PKCα has profound impacts on PD-L1 sEVs secretion, especially in the resting state and in the activated state, when induced by an intracellular calcium rise. Furthermore, our study revealed that PKCα regulates PD-L1 expression and PD-L1 sEVs secretion by influencing STAT1 phosphorylation and nuclear translocation in a p53-dependent manner. Notably, p53 can regulate STAT1 phosphorylation and nuclear localization, but it does not affect PKCα expression. This suggests that PKCα plays a significant role in regulating PD-L1 expression. Our findings suggest that targeting PKCα to modulate PD-L1 dynamics in NSCLC may be a promising therapeutic strategy to enhance the efficacy of immunotherapeutic interventions. |
| format | Article |
| id | doaj-art-a69b7c54e4b343468f89048a23c50c5e |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-a69b7c54e4b343468f89048a23c50c5e2025-01-19T12:40:52ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111510.1038/s41419-025-07341-5PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent mannerRen Zhang0Weilin Liao1Xi Chen2Junyi Wang3Jiaqi Li4Geer Chen5Weiyu Wu6Xiaoxuan Wang7Yao Zhang8Ziyu Chen9Xiaoyu Zhu10Zicong Lin11Yizhun Zhu12Lijuan Ma13Haijie Yu14School of Pharmacy, Faculty of Medicine & State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyDr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologySchool of Pharmacy, Faculty of Medicine & State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologySchool of Pharmacy, Faculty of Medicine & State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologySchool of Pharmacy, Faculty of Medicine & State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and TechnologyAbstract Small extracellular vesicles (sEVs), carrying PD-L1, have been implicated in immune evasion and tumor progression. However, understanding how PD-L1 sEVs are secreted still needs to be improved. We found that the secretion dynamics of PD-L1 sEVs is similar to that of other sEVs. Intracellular calcium and the associated downstream PKC signaling plays pivotal roles in releasing PD-L1 sEVs in non-small cell lung cancer cells (NSCLC). Particularly, we observed that knocking down PKCα has profound impacts on PD-L1 sEVs secretion, especially in the resting state and in the activated state, when induced by an intracellular calcium rise. Furthermore, our study revealed that PKCα regulates PD-L1 expression and PD-L1 sEVs secretion by influencing STAT1 phosphorylation and nuclear translocation in a p53-dependent manner. Notably, p53 can regulate STAT1 phosphorylation and nuclear localization, but it does not affect PKCα expression. This suggests that PKCα plays a significant role in regulating PD-L1 expression. Our findings suggest that targeting PKCα to modulate PD-L1 dynamics in NSCLC may be a promising therapeutic strategy to enhance the efficacy of immunotherapeutic interventions.https://doi.org/10.1038/s41419-025-07341-5 |
| spellingShingle | Ren Zhang Weilin Liao Xi Chen Junyi Wang Jiaqi Li Geer Chen Weiyu Wu Xiaoxuan Wang Yao Zhang Ziyu Chen Xiaoyu Zhu Zicong Lin Yizhun Zhu Lijuan Ma Haijie Yu PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner Cell Death and Disease |
| title | PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner |
| title_full | PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner |
| title_fullStr | PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner |
| title_full_unstemmed | PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner |
| title_short | PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner |
| title_sort | pkcα regulates the secretion of pdl1 carrying small extracellular vesicles in a p53 dependent manner |
| url | https://doi.org/10.1038/s41419-025-07341-5 |
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