journal article·2023-12Open access

The PERK Branch of the Unfolded Protein Response Safeguards Protein Homeostasis and Mesendoderm Specification of Human Pluripotent Stem Cells

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

Advanced Science· Volume 10· Issue 35

Abstract

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.
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Research context

OpenAlex topics: Endoplasmic Reticulum Stress and Disease · Viral Infectious Diseases and Gene Expression in Insects · Signaling Pathways in Disease

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Advanced Medical Technology Center Zhongshan School of Medicine and the First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510080 P. R. China

Key Laboratory for Stem Cells and Tissue Engineering Sun Yat‐Sen University Ministry of Education Guangzhou 510080 P. R. China

Department of Clinical Laboratory The First Affiliated Hospital of Anhui Medical University Hefei 230022 P. R. China

Prenatal Diagnosis Center Department of Obstetrics and Gynecology The First Affiliated Hospital of Anhui Medical University Hefei 230022 P. R. China

Department of Medical Informatics Zhongshan School of Medicine Sun Yat‐Sen University Guangzhou 510080 P. R. China

Guangzhou 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. China

National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 P. R. China

College of Life Sciences University of Chinese Academy of Sciences Beijing 100049 P. R. China

School of Health and Life Sciences University of Health and Rehabilitation Sciences Shandong 266071 China

Funding

National Basic Research Program of China · National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province · Qingdao Municipal Science and Technology Bureau

References (91)

Show source-provided references
1. Sherman L. S. · 2001
2. 10.1038/nature0680110.1038/nature06801 ↗
3. 10.1016/j.stem.2011.12.01310.1016/j.stem.2011.12.013 ↗
4. 10.1126/science.aac435410.1126/science.aac4354 ↗
5. 10.1111/febs.1381010.1111/febs.13810 ↗
6. 10.1146/annurev-biochem-060614-03395510.1146/annurev-biochem-060614-033955 ↗
7. 10.1016/j.cell.2012.08.02710.1016/j.cell.2012.08.027 ↗
8. 10.1016/j.cell.2012.07.03510.1016/j.cell.2012.07.035 ↗
9. Consortium T. P. · bioRxiv · 2023
10. 10.1126/science.120903810.1126/science.1209038 ↗
11. 10.1038/nrm327010.1038/nrm3270 ↗
12. 10.5966/sctm.2015-042810.5966/sctm.2015-0428 ↗
13. 10.1002/biot.20140029110.1002/biot.201400291 ↗
14. 10.1016/j.stem.2016.01.02210.1016/j.stem.2016.01.022 ↗
15. 10.1074/jbc.273.50.3374110.1074/jbc.273.50.33741 ↗
16. 10.1053/j.gastro.2020.06.08810.1053/j.gastro.2020.06.088 ↗
17. 10.1007/s00210-009-0453-510.1007/s00210-009-0453-5 ↗
18. 10.1093/bioinformatics/btu04810.1093/bioinformatics/btu048 ↗
19. 10.1073/pnas.120025010910.1073/pnas.1200250109 ↗
20. 10.1146/annurev-chembioeng-092120-03392210.1146/annurev-chembioeng-092120-033922 ↗
21. 10.1007/s00424-021-02578-310.1007/s00424-021-02578-3 ↗
22. 10.1016/j.stem.2017.07.00310.1016/j.stem.2017.07.003 ↗
23. 10.1016/j.cell.2021.04.03410.1016/j.cell.2021.04.034 ↗
24. 10.1016/j.cell.2016.06.01110.1016/j.cell.2016.06.011 ↗
25. 10.1126/science.aag304810.1126/science.aag3048 ↗
26. 10.1038/s41580-020-0250-z10.1038/s41580-020-0250-z ↗
27. 10.1038/s41422-020-0292-y10.1038/s41422-020-0292-y ↗
28. 10.1002/biot.20180072510.1002/biot.201800725 ↗
29. 10.1016/j.cell.2014.07.02110.1016/j.cell.2014.07.021 ↗
30. 10.1016/j.cell.2014.07.02010.1016/j.cell.2014.07.020 ↗
31. 10.1093/nar/gky22110.1093/nar/gky221 ↗
32. 10.1242/dev.0200510.1242/dev.02005 ↗
33. 10.1038/nbt.232910.1038/nbt.2329 ↗
34. 10.1073/pnas.040054110110.1073/pnas.0400541101 ↗
35. 10.1038/nrm219910.1038/nrm2199 ↗
36. 10.1038/ncb273810.1038/ncb2738 ↗
37. 10.1083/jcb.20040800310.1083/jcb.200408003 ↗
38. 10.1016/j.stemcr.2014.02.01010.1016/j.stemcr.2014.02.010 ↗
39. 10.1242/dev.0215710.1242/dev.02157 ↗
40. 10.7554/eLife.0682110.7554/eLife.06821 ↗
41. 10.1073/pnas.132369711110.1073/pnas.1323697111 ↗
42. 10.1016/j.ydbio.2011.09.00510.1016/j.ydbio.2011.09.005 ↗
43. 10.1016/j.celrep.2016.12.06010.1016/j.celrep.2016.12.060 ↗
44. 10.1523/JNEUROSCI.4011-10.201110.1523/JNEUROSCI.4011-10.2011 ↗
45. 10.1016/j.molcel.2019.06.02410.1016/j.molcel.2019.06.024 ↗
46. 10.1523/JNEUROSCI.4556-05.200610.1523/JNEUROSCI.4556-05.2006 ↗
47. 10.1093/nar/gkm63310.1093/nar/gkm633 ↗
48. 10.1038/s41467-019-09483-510.1038/s41467-019-09483-5 ↗
49. 10.1093/nar/gkx108110.1093/nar/gkx1081 ↗
50. 10.1146/annurev-physiol-020911-15324210.1146/annurev-physiol-020911-153242 ↗
51. 10.1038/sj.emboj.760090310.1038/sj.emboj.7600903 ↗
52. 10.1016/j.cmet.2006.07.00710.1016/j.cmet.2006.07.007 ↗
53. 10.1016/S1097-2765(01)00264-710.1016/S1097-2765(01)00264-7 ↗
54. 10.1139/y11-01910.1139/y11-019 ↗
55. 10.1152/physiol.00034.201210.1152/physiol.00034.2012 ↗
56. Arrieta A. · Curr. Top. Microbiol. Immunol. · 2018 · 414 · 193
57. 10.1242/dev.13682010.1242/dev.136820 ↗
58. 10.1038/s41598-020-77199-410.1038/s41598-020-77199-4 ↗
59. 10.1126/scisignal.aan578510.1126/scisignal.aan5785 ↗
60. 10.1161/HYPERTENSIONAHA.114.0381110.1161/HYPERTENSIONAHA.114.03811 ↗
61. 10.1161/CIRCRESAHA.118.31385410.1161/CIRCRESAHA.118.313854 ↗
62. 10.1161/CIRCULATIONAHA.118.03892410.1161/CIRCULATIONAHA.118.038924 ↗
63. 10.1038/nature1322810.1038/nature13228 ↗
64. 10.7554/eLife.2287110.7554/eLife.22871 ↗
65. 10.1371/journal.pgen.100522010.1371/journal.pgen.1005220 ↗
66. 10.1016/j.cell.2016.11.04810.1016/j.cell.2016.11.048 ↗
67. 10.1038/ni.322510.1038/ni.3225 ↗
68. 10.1016/j.biomaterials.2013.12.06710.1016/j.biomaterials.2013.12.067 ↗
69. 10.1016/S1097-2765(03)00105-910.1016/S1097-2765(03)00105-9 ↗
70. 10.1038/s41598-021-93663-110.1038/s41598-021-93663-1 ↗
71. 10.1002/emmm.20110062610.1002/emmm.201100626 ↗
72. 10.1038/nature0509610.1038/nature05096 ↗
73. 10.1038/s41573-019-0026-310.1038/s41573-019-0026-3 ↗
74. 10.1038/nrm.2017.7710.1038/nrm.2017.77 ↗
75. 10.1093/nar/gkaa104310.1093/nar/gkaa1043 ↗
76. 10.1161/CIRCGENETICS.114.00091810.1161/CIRCGENETICS.114.000918 ↗
77. 10.1016/j.stem.2012.09.01310.1016/j.stem.2012.09.013 ↗
78. 10.1038/s41598-017-02456-y10.1038/s41598-017-02456-y ↗
79. 10.1038/nprot.2008.7310.1038/nprot.2008.73 ↗
80. 10.1093/bioinformatics/bts63510.1093/bioinformatics/bts635 ↗
81. 10.1186/1471-2105-12-32310.1186/1471-2105-12-323 ↗
82. 10.1186/s13059-014-0550-810.1186/s13059-014-0550-8 ↗
83. 10.1089/omi.2011.011810.1089/omi.2011.0118 ↗
84. 10.1038/nprot.2017.02210.1038/nprot.2017.022 ↗
85. 10.1038/nprot.2006.9810.1038/nprot.2006.98 ↗
86. 10.1093/bioinformatics/bty56010.1093/bioinformatics/bty560 ↗
87. Li H. · arXiv · 2013
88. 10.1016/j.molcel.2010.05.00410.1016/j.molcel.2010.05.004 ↗
89. 10.1093/bioinformatics/btv14510.1093/bioinformatics/btv145 ↗
90. 10.1038/s41467-019-09234-610.1038/s41467-019-09234-6 ↗
91. 10.1038/ng.12710.1038/ng.127 ↗