Research status and progress of endoplasmic reticulum stress in scleral remodeling_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Zhao ^1,2 , Xie Bing ¹ ,  Cai Shanjun ¹

1. Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University (Guizhou Ophthalmology Hospital & Guizhou Branch of National Ophthalmology Clinical Research Center & Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi 563003, China;
2. Department of Clinical Medicine, The First Clinical College of Zunyi Medical University, Zunyi 563003, China;

Corresponding author：

Cai Shanjun, Email: caishanjun@163.com

Keywords：

Endoplasmic reticulum stress; Sclera remodeling; Myopia; Inositol-requiring protein 1; Protein kinase RNA-like endoplasmic reticulum kinase; Activating transcription factor 6; Unfolded protein response; Review

DOI：

10.3760/cma.j.cn511434-20221201-00634

Video：

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Abstract Full text Figures/Tables Video References Cited by

The occurrence and development of myopia is closely related to scleral remodeling. Therefore, in order to effectively prevent and cure myopia, it is very important to clarify the mechanism of scleral remodeling. In recent years, Chinese scholars have found that endoplasmic reticulum stress can regulate the expression of apoptotic proteins through the inositol demand protein-1/X box binding protein-1 pathway in the unfolded protein response, thus it is involved in regulating the state of scleral fibroblasts under hypoxia and regulating the occurrence and development of scleral remodeling. At the same time, some studies have found that inhibiting and knocking out protein kinase RNA-like endoplasmic reticulum kinase and activated transcription factor 6 in endoplasmic reticulum stress can effectively inhibit the growth of ocular axis. This proves that endoplasmic reticulum stress plays an important role in the occurrence and development of scleral remodeling. However, the comprehensive analysis of endoplasmic reticulum stress and scleral remodeling has not been reported at home and abroad. In-depth analysis of the relationship between endoplasmic reticulum and scleral remodeling is of great significance for the follow-up analysis and study of the mechanism of scleral remodeling.

Citation： Liu Zhao, Xie Bing, Cai Shanjun. Research status and progress of endoplasmic reticulum stress in scleral remodeling. Chinese Journal of Ocular Fundus Diseases, 2023, 39(10): 873-878. doi: 10.3760/cma.j.cn511434-20221201-00634 Copy

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2.	Holden BA, Fricke TR, Wilson DA, et al. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050[J]. Ophthalmology, 2016, 123(5): 1036-1042. DOI: 10.1016/j.ophtha.2016.01.006.
3.	Harper AR, Summers JA. The dynamic sclera: extracellular matrix remodeling in normal ocular growth and myopia development[J]. Exp Eye Res, 2015, 133: 100-111. DOI: 10.1016/j.exer.2014.07.015.
4.	Lenna S, Trojanowska M. The role of endoplasmic reticulum stress and the unfolded protein response in fibrosis[J]. Curr Opin Rheumatol, 2012, 24(6): 663-668. DOI: 10.1097/BOR.0b013e3283588dbb.
5.	Marciniak SJ, Chambers JE, Ron D. Pharmacological targeting of endoplasmic reticulum stress in disease[J]. Nat Rev Drug Discov, 2022, 21(2): 115-140. DOI: 10.1038/s41573-021-00320-3.
6.	Ikeda SI, Kurihara T, Jiang X, et al. Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes[J/OL]. Nat Commun, 2022, 13(1): 5859[2022-10-10]. https://pubmed.ncbi.nlm.nih.gov/36216837/. DOI: 10.1038/s41467-022-33605-1.
7.	Jiang B, Wu ZY, Zhu ZC, et al. Expression and role of specificity protein 1 in the sclera remodeling of experimental myopia in guinea pigs[J]. Int J Ophthalmol, 2017, 10(4): 550-554. DOI: 10.18240/ijo.2017.04.08.
8.	Gentle A, Liu Y, Martin JE, et al. Collagen gene expression and the altered accumulation of scleral collagen during the development of high myopia[J]. J Biol Chem, 2003, 278(19): 16587-16594. DOI: 10.1074/jbc.M300970200.
9.	Ouyang X, Han Y, Xie Y, et al. The collagen metabolism affects the scleral mechanical properties in the different processes of scleral remodeling[J/OL]. Biomed Pharmacother, 2019, 118: 109294[2019-08-09]. https://pubmed.ncbi.nlm.nih.gov/31404770/. DOI: 10.1016/j.biopha.2019.109294.
10.	Metlapally R, Wildsoet CF. Scleral mechanisms underlying ocular growth and myopia[J]. Prog Mol Biol Transl Sci, 2015, 134: 241-248. DOI: 10.1016/bs.pmbts.2015.05.005.
11.	Jonas JB, Xu L. Histological changes of high axial myopia[J]. Eye (Lond), 2014, 28(2): 113-117. DOI: 10.1038/eye.2013.223.
12.	Yu Q, Zhou JB. Scleral remodeling in myopia development[J]. Int J Ophthalmol, 2022, 15(3): 510-514. DOI: 10.18240/ijo.2022.03.21.
13.	Zhou X, Ye C, Wang X, et al. Choroidal blood perfusion as a potential "rapid predictive index" for myopia development and progression[J]. Eye Vis (Lond), 2021, 8(1): 1. DOI: 10.1186/s40662-020-00224-0.
14.	Wu H, Chen W, Zhao F, et al. Scleral hypoxia is a target for myopia control[J/OL]. Proc Natl Acad Sci USA, 2018, 115(30): E7091-7100[2018-07-24]. https://pubmed.ncbi.nlm.nih.gov/29987045/. DOI: 10.1073/pnas.1721443115.
15.	Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response[J]. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529. DOI: 10.1038/nrm2199.
16.	Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease[J]. J Hepatol, 2011, 54(4): 795-809. DOI: 10.1016/j.jhep.2010.11.005.
17.	Lee CL, Veerbeek JHW, Rana TK, et al. Role of endoplasmic reticulum stress in proinflammatory cytokine-mediated inhibition of trophoblast invasion in placenta-related complications of pregnancy[J]. Am J Pathol, 2019, 189(2): 467-478. DOI: 10.1016/j.ajpath.2018.10.015.
18.	Zhao F, Zhou Q, Reinach PS, et al. Cause and effect relationship between changes in scleral matrix metallopeptidase-2 expression and myopia development in mice[J]. Am J Pathol, 2018, 188(8): 1754-1767. DOI: 10.1016/j.ajpath.2018.04.011.
19.	Anelli T, Sitia R. Protein quality control in the early secretory pathway[J]. EMBO J, 2008, 27(2): 315-327. DOI: 10.1038/sj.emboj.7601974.
20.	Hetz C, Martinon F, Rodriguez D, et al. The unfolded protein response: integrating stress signals through the stress sensor IRE1[J]. Physiol Rev, 2011, 91(4): 1219-1243. DOI: 10.1152/physrev.00001.2011.
21.	Yan M, Shu S, Guo C, et al. Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury[J]. Ann Med, 2018, 50(5): 381-390. DOI: 10.1080/07853890.2018.1489142.
22.	Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation[J]. Science, 2011, 334(6059): 1081-1086. DOI: 10.1126/science.1209038.
23.	Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program[J]. Cell Death Differ, 2004, 11(4): 372-380. DOI: 10.1038/sj.cdd.4401378.
24.	陈庆中. 豚鼠实验性近视巩膜基质重塑中内质网应激与TGF-β1的交互作用及机制[D]. 上海: 上海交通大学, 2017.Chen QZ. The regulatory role and mechanism of crosstalk between endoplasmic reticulum stress and TGF-β1 on scleral fibroblast extracellular matrix remodeling of experimental myopic guinea pig[D]. Shanghai: Shanghai Jiao Tong University, 2017.
25.	唐晓兰, 刘玲, 杨倩颖, 等. 缺氧对巩膜成纤维细胞内质网应激反应的激活作用及其对巩膜重塑的影响[J]. 眼科新进展, 2022, 42(7): 529-533. DOI: 10.13389/j.cnki.rao.2022.0108.Tang XL, Liu L, Yang QY, et al. Effects of hypoxia on the activation of endoplasmic reticulum stress response and on the scleral remodeling in human fetal scleral fibroblasts[J]. Rec Adv Ophthalmol, 2022, 42(7): 529-533. DOI: 10.13389/j.cnki.rao.2022.0108.
26.	Karagöz GE, Acosta-Alvear D, Walter P. The unfolded protein response: detecting and responding to fluctuations in the protein-folding capacity of the endoplasmic reticulum[J/OL]. Cold Spring Harb Perspect Biol, 2019, 11(9): a033886[2019-09-03]. https://pubmed.ncbi.nlm.nih.gov/30670466/. DOI: 10.1101/cshperspect.a033886.
27.	Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA[J]. Nature, 2002, 415(6867): 92-96. DOI: 10.1038/415092a.
28.	Lee K, Tirasophon W, Shen X, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response[J]. Genes Dev, 2002, 16(4): 452-466. DOI: 10.1101/gad.964702.
29.	Acosta-Alvear D, Zhou Y, Blais A, et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks[J]. Mol Cell, 2007, 27(1): 53-66. DOI: 10.1016/j.molcel.2007.06.011.
30.	Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond[J]. Nat Rev Mol Cell Biol, 2012, 13(2): 89-102. DOI: 10.1038/nrm3270.
31.	Han D, Lerner AG, Vande Walle L, et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates[J]. Cell, 2009, 138(3): 562-575. DOI: 10.1016/j.cell.2009.07.017.
32.	Hollien J, Lin JH, Li H, et al. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells[J]. J Cell Biol, 2009, 186(3): 323-331. DOI: 10.1083/jcb.200903014.
33.	Maurel M, Chevet E, Tavernier J, et al. Getting RIDD of RNA: IRE1 in cell fate regulation[J]. Trends Biochem Sci, 2014, 39(5): 245-254. DOI: 10.1016/j.tibs.2014.02.008.
34.	Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats[J]. Genes Dev, 2002, 16(11): 1345-1355. DOI: 10.1101/gad.992302.
35.	Cornejo VH, Pihán P, Vidal RL, et al. Role of the unfolded protein response in organ physiology: lessons from mouse models[J]. IUBMB Life, 2013, 65(12): 962-975. DOI: 10.1002/iub.1224.
36.	Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response[J]. J Cell Biol, 2004, 167(1): 27-33. DOI: 10.1083/jcb.200408003.
37.	Liu CY, Schröder M, Kaufman RJ. Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum[J]. J Biol Chem, 2000, 275(32): 24881-24885. DOI: 10.1074/jbc.M004454200.
38.	Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology[J]. Annu Rev Pathol, 2015, 10: 173-194. DOI: 10.1146/annurev-pathol-012513-104649.
39.	Emanuelli G, Nassehzadeh-Tabriz N, Morrell NW, et al. The integrated stress response in pulmonary disease[J/OL]. Eur Respir Rev, 2020, 29(157): 200184[2020-10-01]. https://pubmed.ncbi.nlm.nih.gov/33004527/. DOI: 10.1183/16000617.0184-2020.
40.	Urra H, Dufey E, Lisbona F, et al. When ER stress reaches a dead end[J]. Biochim Biophys Acta, 2013, 1833(12): 3507-3517. DOI: 10.1016/j.bbamcr.2013.07.024.
41.	Ren Y, Yang X, Luo Z, et al. HIF-1α aggravates pathologic myopia through the miR-150-5p/LAMA4/p38 MAPK signaling axis[J]. Mol Cell Biochem, 2022, 477(4): 1065-1074. DOI: 10.1007/s11010-021-04305-z.
42.	Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress[J]. Mol Biol Cell, 1999, 10(11): 3787-3799. DOI: 10.1091/mbc.10.11.3787.
43.	Schindler AJ, Schekman R. In vitro reconstitution of ER-stress induced ATF6 transport in COPII vesicles[J]. Proc Natl Acad Sci USA, 2009, 106(42): 17775-17780. DOI: 10.1073/pnas.0910342106.
44.	Yamamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1[J]. Dev Cell, 2007, 13(3): 365-376. DOI: 10.1016/j.devcel.2007.07.018.
45.	Shoulders MD, Ryno LM, Genereux JC, et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments[J]. Cell Rep, 2013, 3(4): 1279-1292. DOI: 10.1016/j.celrep.2013.03.024.
46.	Xiong Z, Jiang R, Zhang P, et al. Transmission of ER stress response by ATF6 promotes endochondral bone growth[J]. J Orthop Surg Res, 2015, 10: 141. DOI: 10.1186/s13018-015-0284-7.
47.	Qiu C, Yao J, Zhang X, et al. The dynamic scleral extracellular matrix alterations in chronic ocular hypertension model of rats[J]. Front Physiol, 2020, 11: 682. DOI: 10.3389/fphys.2020.00682.
48.	Murphy G, Stanton H, Cowell S, et al. Mechanisms for pro matrix metalloproteinase activation[J]. APMIS, 1999, 107(1): 38-44. DOI: 10.1111/j.1699-0463.1999.tb01524.x.

1. Morgan IG, French AN, Ashby RS, et al. The epidemics of myopia: aetiology and prevention[J]. Prog Retin Eye Res, 2018, 62: 134-149. DOI: 10.1016/j.preteyeres.2017.09.004.
2. Holden BA, Fricke TR, Wilson DA, et al. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050[J]. Ophthalmology, 2016, 123(5): 1036-1042. DOI: 10.1016/j.ophtha.2016.01.006.
3. Harper AR, Summers JA. The dynamic sclera: extracellular matrix remodeling in normal ocular growth and myopia development[J]. Exp Eye Res, 2015, 133: 100-111. DOI: 10.1016/j.exer.2014.07.015.
4. Lenna S, Trojanowska M. The role of endoplasmic reticulum stress and the unfolded protein response in fibrosis[J]. Curr Opin Rheumatol, 2012, 24(6): 663-668. DOI: 10.1097/BOR.0b013e3283588dbb.
5. Marciniak SJ, Chambers JE, Ron D. Pharmacological targeting of endoplasmic reticulum stress in disease[J]. Nat Rev Drug Discov, 2022, 21(2): 115-140. DOI: 10.1038/s41573-021-00320-3.
6. Ikeda SI, Kurihara T, Jiang X, et al. Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes[J/OL]. Nat Commun, 2022, 13(1): 5859[2022-10-10]. https://pubmed.ncbi.nlm.nih.gov/36216837/. DOI: 10.1038/s41467-022-33605-1.
7. Jiang B, Wu ZY, Zhu ZC, et al. Expression and role of specificity protein 1 in the sclera remodeling of experimental myopia in guinea pigs[J]. Int J Ophthalmol, 2017, 10(4): 550-554. DOI: 10.18240/ijo.2017.04.08.
8. Gentle A, Liu Y, Martin JE, et al. Collagen gene expression and the altered accumulation of scleral collagen during the development of high myopia[J]. J Biol Chem, 2003, 278(19): 16587-16594. DOI: 10.1074/jbc.M300970200.
9. Ouyang X, Han Y, Xie Y, et al. The collagen metabolism affects the scleral mechanical properties in the different processes of scleral remodeling[J/OL]. Biomed Pharmacother, 2019, 118: 109294[2019-08-09]. https://pubmed.ncbi.nlm.nih.gov/31404770/. DOI: 10.1016/j.biopha.2019.109294.
10. Metlapally R, Wildsoet CF. Scleral mechanisms underlying ocular growth and myopia[J]. Prog Mol Biol Transl Sci, 2015, 134: 241-248. DOI: 10.1016/bs.pmbts.2015.05.005.
11. Jonas JB, Xu L. Histological changes of high axial myopia[J]. Eye (Lond), 2014, 28(2): 113-117. DOI: 10.1038/eye.2013.223.
12. Yu Q, Zhou JB. Scleral remodeling in myopia development[J]. Int J Ophthalmol, 2022, 15(3): 510-514. DOI: 10.18240/ijo.2022.03.21.
13. Zhou X, Ye C, Wang X, et al. Choroidal blood perfusion as a potential "rapid predictive index" for myopia development and progression[J]. Eye Vis (Lond), 2021, 8(1): 1. DOI: 10.1186/s40662-020-00224-0.
14. Wu H, Chen W, Zhao F, et al. Scleral hypoxia is a target for myopia control[J/OL]. Proc Natl Acad Sci USA, 2018, 115(30): E7091-7100[2018-07-24]. https://pubmed.ncbi.nlm.nih.gov/29987045/. DOI: 10.1073/pnas.1721443115.
15. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response[J]. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529. DOI: 10.1038/nrm2199.
16. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease[J]. J Hepatol, 2011, 54(4): 795-809. DOI: 10.1016/j.jhep.2010.11.005.
17. Lee CL, Veerbeek JHW, Rana TK, et al. Role of endoplasmic reticulum stress in proinflammatory cytokine-mediated inhibition of trophoblast invasion in placenta-related complications of pregnancy[J]. Am J Pathol, 2019, 189(2): 467-478. DOI: 10.1016/j.ajpath.2018.10.015.
18. Zhao F, Zhou Q, Reinach PS, et al. Cause and effect relationship between changes in scleral matrix metallopeptidase-2 expression and myopia development in mice[J]. Am J Pathol, 2018, 188(8): 1754-1767. DOI: 10.1016/j.ajpath.2018.04.011.
19. Anelli T, Sitia R. Protein quality control in the early secretory pathway[J]. EMBO J, 2008, 27(2): 315-327. DOI: 10.1038/sj.emboj.7601974.
20. Hetz C, Martinon F, Rodriguez D, et al. The unfolded protein response: integrating stress signals through the stress sensor IRE1[J]. Physiol Rev, 2011, 91(4): 1219-1243. DOI: 10.1152/physrev.00001.2011.
21. Yan M, Shu S, Guo C, et al. Endoplasmic reticulum stress in ischemic and nephrotoxic acute kidney injury[J]. Ann Med, 2018, 50(5): 381-390. DOI: 10.1080/07853890.2018.1489142.
22. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation[J]. Science, 2011, 334(6059): 1081-1086. DOI: 10.1126/science.1209038.
23. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program[J]. Cell Death Differ, 2004, 11(4): 372-380. DOI: 10.1038/sj.cdd.4401378.
24. 陈庆中. 豚鼠实验性近视巩膜基质重塑中内质网应激与TGF-β1的交互作用及机制[D]. 上海: 上海交通大学, 2017.Chen QZ. The regulatory role and mechanism of crosstalk between endoplasmic reticulum stress and TGF-β1 on scleral fibroblast extracellular matrix remodeling of experimental myopic guinea pig[D]. Shanghai: Shanghai Jiao Tong University, 2017.
25. 唐晓兰, 刘玲, 杨倩颖, 等. 缺氧对巩膜成纤维细胞内质网应激反应的激活作用及其对巩膜重塑的影响[J]. 眼科新进展, 2022, 42(7): 529-533. DOI: 10.13389/j.cnki.rao.2022.0108.Tang XL, Liu L, Yang QY, et al. Effects of hypoxia on the activation of endoplasmic reticulum stress response and on the scleral remodeling in human fetal scleral fibroblasts[J]. Rec Adv Ophthalmol, 2022, 42(7): 529-533. DOI: 10.13389/j.cnki.rao.2022.0108.
26. Karagöz GE, Acosta-Alvear D, Walter P. The unfolded protein response: detecting and responding to fluctuations in the protein-folding capacity of the endoplasmic reticulum[J/OL]. Cold Spring Harb Perspect Biol, 2019, 11(9): a033886[2019-09-03]. https://pubmed.ncbi.nlm.nih.gov/30670466/. DOI: 10.1101/cshperspect.a033886.
27. Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA[J]. Nature, 2002, 415(6867): 92-96. DOI: 10.1038/415092a.
28. Lee K, Tirasophon W, Shen X, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response[J]. Genes Dev, 2002, 16(4): 452-466. DOI: 10.1101/gad.964702.
29. Acosta-Alvear D, Zhou Y, Blais A, et al. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks[J]. Mol Cell, 2007, 27(1): 53-66. DOI: 10.1016/j.molcel.2007.06.011.
30. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond[J]. Nat Rev Mol Cell Biol, 2012, 13(2): 89-102. DOI: 10.1038/nrm3270.
31. Han D, Lerner AG, Vande Walle L, et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates[J]. Cell, 2009, 138(3): 562-575. DOI: 10.1016/j.cell.2009.07.017.
32. Hollien J, Lin JH, Li H, et al. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells[J]. J Cell Biol, 2009, 186(3): 323-331. DOI: 10.1083/jcb.200903014.
33. Maurel M, Chevet E, Tavernier J, et al. Getting RIDD of RNA: IRE1 in cell fate regulation[J]. Trends Biochem Sci, 2014, 39(5): 245-254. DOI: 10.1016/j.tibs.2014.02.008.
34. Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats[J]. Genes Dev, 2002, 16(11): 1345-1355. DOI: 10.1101/gad.992302.
35. Cornejo VH, Pihán P, Vidal RL, et al. Role of the unfolded protein response in organ physiology: lessons from mouse models[J]. IUBMB Life, 2013, 65(12): 962-975. DOI: 10.1002/iub.1224.
36. Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response[J]. J Cell Biol, 2004, 167(1): 27-33. DOI: 10.1083/jcb.200408003.
37. Liu CY, Schröder M, Kaufman RJ. Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum[J]. J Biol Chem, 2000, 275(32): 24881-24885. DOI: 10.1074/jbc.M004454200.
38. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology[J]. Annu Rev Pathol, 2015, 10: 173-194. DOI: 10.1146/annurev-pathol-012513-104649.
39. Emanuelli G, Nassehzadeh-Tabriz N, Morrell NW, et al. The integrated stress response in pulmonary disease[J/OL]. Eur Respir Rev, 2020, 29(157): 200184[2020-10-01]. https://pubmed.ncbi.nlm.nih.gov/33004527/. DOI: 10.1183/16000617.0184-2020.
40. Urra H, Dufey E, Lisbona F, et al. When ER stress reaches a dead end[J]. Biochim Biophys Acta, 2013, 1833(12): 3507-3517. DOI: 10.1016/j.bbamcr.2013.07.024.
41. Ren Y, Yang X, Luo Z, et al. HIF-1α aggravates pathologic myopia through the miR-150-5p/LAMA4/p38 MAPK signaling axis[J]. Mol Cell Biochem, 2022, 477(4): 1065-1074. DOI: 10.1007/s11010-021-04305-z.
42. Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress[J]. Mol Biol Cell, 1999, 10(11): 3787-3799. DOI: 10.1091/mbc.10.11.3787.
43. Schindler AJ, Schekman R. In vitro reconstitution of ER-stress induced ATF6 transport in COPII vesicles[J]. Proc Natl Acad Sci USA, 2009, 106(42): 17775-17780. DOI: 10.1073/pnas.0910342106.
44. Yamamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1[J]. Dev Cell, 2007, 13(3): 365-376. DOI: 10.1016/j.devcel.2007.07.018.
45. Shoulders MD, Ryno LM, Genereux JC, et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments[J]. Cell Rep, 2013, 3(4): 1279-1292. DOI: 10.1016/j.celrep.2013.03.024.
46. Xiong Z, Jiang R, Zhang P, et al. Transmission of ER stress response by ATF6 promotes endochondral bone growth[J]. J Orthop Surg Res, 2015, 10: 141. DOI: 10.1186/s13018-015-0284-7.
47. Qiu C, Yao J, Zhang X, et al. The dynamic scleral extracellular matrix alterations in chronic ocular hypertension model of rats[J]. Front Physiol, 2020, 11: 682. DOI: 10.3389/fphys.2020.00682.
48. Murphy G, Stanton H, Cowell S, et al. Mechanisms for pro matrix metalloproteinase activation[J]. APMIS, 1999, 107(1): 38-44. DOI: 10.1111/j.1699-0463.1999.tb01524.x.

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