The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells
Abstract Cardiac development involves large‐scale rearrangements of the proteome. How the developing cardiac cells maintain the integrity of the proteome during the rapid lineage transition remains unclear. Here it is shown that proteotoxic stress visualized by the misfolded and/or aggregated protei...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-12-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202303799 |
| _version_ | 1797389584136404992 |
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| author | Fang Liu Zhun Liu Weisheng Cheng Qingquan Zhao Xinyu Zhang He Zhang Miao Yu He Xu Yichen Gao Qianrui Jiang Guojun Shi Likun Wang Shanshan Gu Jia Wang Nan Cao Zhongyan Chen |
| author_facet | Fang Liu Zhun Liu Weisheng Cheng Qingquan Zhao Xinyu Zhang He Zhang Miao Yu He Xu Yichen Gao Qianrui Jiang Guojun Shi Likun Wang Shanshan Gu Jia Wang Nan Cao Zhongyan Chen |
| author_sort | Fang Liu |
| collection | DOAJ |
| description | Abstract Cardiac development involves large‐scale rearrangements of the proteome. How the developing cardiac cells maintain the integrity of the proteome during the rapid lineage transition remains unclear. Here it is shown that proteotoxic stress visualized by the misfolded and/or aggregated proteins appears during early cardiac differentiation of human pluripotent stem cells and is resolved by activation of the PERK branch of unfolded protein response (UPR). PERK depletion increases misfolded and/or aggregated protein accumulation, leading to pluripotency exit defect and impaired mesendoderm specification of human pluripotent stem cells. Mechanistically, it is found that PERK safeguards mesendoderm specification through its conserved downstream effector ATF4, which subsequently activates a novel transcriptional target WARS1, to cope with the differentiation‐induced proteotoxic stress. The results indicate that protein quality control represents a previously unrecognized core component of the cardiogenic regulatory network. Broadly, these findings provide a framework for understanding how UPR is integrated into the developmental program by activating the PERK‐ATF4‐WARS1 axis. |
| first_indexed | 2024-03-08T22:59:03Z |
| format | Article |
| id | doaj.art-ed4d6c08cc344c15ad5d257163fe6f38 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T22:59:03Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-ed4d6c08cc344c15ad5d257163fe6f382023-12-16T04:16:14ZengWileyAdvanced Science2198-38442023-12-011035n/an/a10.1002/advs.202303799The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem CellsFang Liu0Zhun Liu1Weisheng Cheng2Qingquan Zhao3Xinyu Zhang4He Zhang5Miao Yu6He Xu7Yichen Gao8Qianrui Jiang9Guojun Shi10Likun Wang11Shanshan Gu12Jia Wang13Nan Cao14Zhongyan Chen15Advanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaPrenatal Diagnosis Center Department of Obstetrics and Gynecology The First Affiliated Hospital of Anhui Medical University Hefei 230022 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaGuangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research Guangdong Provincial Key Laboratory of Diabetology The Third Affiliated Hospital of Sun Yat‐Sen University Guangdong 510080 P. R. ChinaNational Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaSchool of Health and Life Sciences University of Health and Rehabilitation Sciences Shandong 266071 ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAdvanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. ChinaAbstract Cardiac development involves large‐scale rearrangements of the proteome. How the developing cardiac cells maintain the integrity of the proteome during the rapid lineage transition remains unclear. Here it is shown that proteotoxic stress visualized by the misfolded and/or aggregated proteins appears during early cardiac differentiation of human pluripotent stem cells and is resolved by activation of the PERK branch of unfolded protein response (UPR). PERK depletion increases misfolded and/or aggregated protein accumulation, leading to pluripotency exit defect and impaired mesendoderm specification of human pluripotent stem cells. Mechanistically, it is found that PERK safeguards mesendoderm specification through its conserved downstream effector ATF4, which subsequently activates a novel transcriptional target WARS1, to cope with the differentiation‐induced proteotoxic stress. The results indicate that protein quality control represents a previously unrecognized core component of the cardiogenic regulatory network. Broadly, these findings provide a framework for understanding how UPR is integrated into the developmental program by activating the PERK‐ATF4‐WARS1 axis.https://doi.org/10.1002/advs.202303799human pluripotent stem cellsmesendoderm specificationPERKproteostasisunfolded protein response |
| spellingShingle | Fang Liu Zhun Liu Weisheng Cheng Qingquan Zhao Xinyu Zhang He Zhang Miao Yu He Xu Yichen Gao Qianrui Jiang Guojun Shi Likun Wang Shanshan Gu Jia Wang Nan Cao Zhongyan Chen The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells Advanced Science human pluripotent stem cells mesendoderm specification PERK proteostasis unfolded protein response |
| title | The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells |
| title_full | The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells |
| title_fullStr | The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells |
| title_full_unstemmed | The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells |
| title_short | The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells |
| title_sort | perk branch of the unfolded protein response safeguards protein homeostasis and mesendoderm specification of human pluripotent stem cells |
| topic | human pluripotent stem cells mesendoderm specification PERK proteostasis unfolded protein response |
| url | https://doi.org/10.1002/advs.202303799 |
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