Volume 42 Issue 3
May  2021
Turn off MathJax
Article Contents
Zhe-Kun Jia, Chen-Xi Fu, Ai-Ling Wang, Ke Yao, Xiang-Jun Chen. Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model. Zoological Research, 2021, 42(3): 300-309. doi: 10.24272/j.issn.2095-8137.2020.354
Citation: Zhe-Kun Jia, Chen-Xi Fu, Ai-Ling Wang, Ke Yao, Xiang-Jun Chen. Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model. Zoological Research, 2021, 42(3): 300-309. doi: 10.24272/j.issn.2095-8137.2020.354

Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

doi: 10.24272/j.issn.2095-8137.2020.354
Funds:  This study was supported by the National Natural Science Foundation of China (31872724, 81900837, 81870641, 82070939) and Zhejiang Province Key Research and Development Program (2019C03091, 2020C03035)
More Information
  • As small heat shock proteins, α-crystallins function as molecular chaperones and inhibit the misfolding and aggregation of β/γ-crystallins. Genetic mutations of CRYAA are associated with protein aggregation and cataract occurrence. One possible process underlying cataract formation is that endoplasmic reticulum stress (ERS) induces the unfolded protein response (UPR), leading to apoptosis. However, the pathogenic mechanism related to this remains unexplored. Here, we successfully constructed a cataract-causing CRYAA (Y118D) mutant mouse model, in which the lenses of the CRYAA-Y118D mutant mice showed severe posterior rupture, abnormal morphological changes, and aberrant arrangement of crystallin fibers. Histological analysis was consistent with the clinical pathological characteristics. We also explored the pathogenic factors involved in cataract development through transcriptome analysis. In addition, based on key pathway analysis, up-regulated genes in CRYAA-Y118D mutant mice were implicated in the ERS-UPR pathway. This study showed that prolonged activation of the UPR pathway and severe stress response can cause proteotoxic and ERS-induced cell death in CRYAA-Y118D mutant mice.
  • loading
  • [1]
    Ahsan SM, Bakthisaran R, Tangirala R, Rao CM. 2021. Nucleosomal association and altered interactome underlie the mechanism of cataract caused by the R54C mutation of αA-crystallin. Biochimica Et Biophysica Acta. General Subjects, 1865(5): 129846. doi: 10.1016/j.bbagen.2021.129846
    [2]
    Al Mamun A, Rahman MM, Zaman S, Munira MS, Uddin MS, Rauf A, et al. 2020. Molecular Insight into the Crosstalk of UPS Components and Alzheimer’s Disease. Current Protein & Peptide Science, 21(12): 1193−1201.
    [3]
    Andley UP. 2009. αA-crystallin R49Cneomutation influences the architecture of lens fiber cell membranes and causes posterior and nuclear cataracts in mice. BMC Ophthalmology, 9(1): 4. doi: 10.1186/1471-2415-9-4
    [4]
    Andley UP, Goldman JW. 2016. Autophagy and UPR in alpha-crystallin mutant knock-in mouse models of hereditary cataracts. Biochimica et Biophysica Acta (BBA) - General Subjects, 1860: 234−239. doi: 10.1016/j.bbagen.2015.06.001
    [5]
    Banh A, Bantseev V, Choh V, Moran KL, Sivak JG. 2006. The lens of the eye as a focusing device and its response to stress. Progress in Retinal and Eye Research, 25(2): 189−206. doi: 10.1016/j.preteyeres.2005.10.001
    [6]
    Bari KJ, Sharma S, Chary KVR. 2019a. Structure of G57W mutant of human γS-crystallin and its involvement in cataract formation. Journal of Structural Biology, 205(3): 72−78. doi: 10.1016/j.jsb.2019.02.003
    [7]
    Bari KJ, Sharma S, Chary KVR. 2019b. Conformational dynamics study on human γS-crystallin as an efficient route to childhood blindness. Biochemical and Biophysical Research Communications, 511(3): 679−684. doi: 10.1016/j.bbrc.2019.02.124
    [8]
    Bartoszewska S, Collawn JF. 2020. Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia. Cellular & Molecular Biology Letters, 25: 18.
    [9]
    Cheng C, Xia C hong, Huang Q, Ding L, Horwitz J, Gong X. 2010. Altered Chaperone-like Activity of α-Crystallins Promotes Cataractogenesis. Journal of Biological Chemistry, 285(52): 41187−41193. doi: 10.1074/jbc.M110.154534
    [10]
    Chothe PP, Thakkar SV, Gnana-Prakasam JP, Ananth S, Hinton DR, Kannan R, et al. 2010. Identification of a Novel Sodium-Coupled Oligopeptide Transporter (SOPT2) in Mouse and Human Retinal Pigment Epithelial Cells. Investigative Opthalmology & Visual Science, 51(1): 413.
    [11]
    Christopher KL, Pedler MG, Shieh B, Ammar DA, Petrash JM, Mueller NH. 2014. Alpha-crystallin-mediated protection of lens cells against heat and oxidative stress-induced cell death. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1843(2): 309−315. doi: 10.1016/j.bbamcr.2013.11.010
    [12]
    Crawford RR, Prescott ET, Sylvester CF, Higdon AN, Shan J, Kilberg MS, et al. 2015. Human CHAC1 Protein Degrades Glutathione, and mRNA Induction Is Regulated by the Transcription Factors ATF4 and ATF3 and a Bipartite ATF/CRE Regulatory Element. Journal of Biological Chemistry, 290(25): 15878−15891. doi: 10.1074/jbc.M114.635144
    [13]
    Delaye M, Tardieu A. 1983. Short-range order of crystallin proteins accounts for eye lens transparency. Nature, 302(5907): 415−417. doi: 10.1038/302415a0
    [14]
    Derham B. 1999. Alpha-Crystallin as a molecular chaperone. Progress in Retinal and Eye Research, 18(4): 463−509. doi: 10.1016/S1350-9462(98)00030-5
    [15]
    Frankfater C, Bozeman SL, Hsu FF, Andley UP. 2020. Alpha-crystallin mutations alter lens metabolites in mouse models of human cataracts. PloS One, 15(8): e0238081. doi: 10.1371/journal.pone.0238081
    [16]
    Fu C, Xu J, Jia Z, Yao K, Chen X. 2021. Cataract-causing mutations L45P and Y46D promote γC-crystallin aggregation by disturbing hydrogen bonds network in the second Greek key motif. International Journal of Biological Macromolecules, 167: 470−478. doi: 10.1016/j.ijbiomac.2020.11.158
    [17]
    Fusakio ME, Willy JA, Wang Y, Mirek ET, Al Baghdadi RJT, Adams CM, et al. 2016. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver (S Wolin, Ed.). Molecular Biology of the Cell, 27(9): 1536−1551. doi: 10.1091/mbc.E16-01-0039
    [18]
    Galluzzi L, De Santi M, Crinelli R, De Marco C, Zaffaroni N, Duranti A, et al. 2012. Induction of Endoplasmic Reticulum Stress Response by the Indole-3-Carbinol Cyclic Tetrameric Derivative CTet in Human Breast Cancer Cell Lines (A Ahmad, Ed.). PLoS ONE, 7(8): e43249. doi: 10.1371/journal.pone.0043249
    [19]
    Graw J, Löster J, Soewarto D, Fuchs H, Meyer B, Reis A, et al. 2001. Characterization of a new, dominant V124E mutation in the mouse alphaA-crystallin-encoding gene. Investigative Ophthalmology & Visual Science, 42(12): 2909−2915.
    [20]
    Hejtmancik JF. 2008. Congenital cataracts and their molecular genetics. Seminars in Cell & Developmental Biology, 19(2): 134−149.
    [21]
    Huang Q, Ding L, Phan KB, Cheng C, Xia CH, Gong X, et al. 2009. Mechanism of Cataract Formation in αA-crystallin Y118D Mutation. Investigative Opthalmology & Visual Science, 50(6): 2919.
    [22]
    Ichimura Y, Komatsu M. 2010. Selective degradation of p62 by autophagy. Seminars in Immunopathology, 32(4): 431−436. doi: 10.1007/s00281-010-0220-1
    [23]
    Ikesugi K, Yamamoto R, Mulhern ML, Shinohara T. 2006. Role of the unfolded protein response (UPR) in cataract formation. Experimental Eye Research, 54(83): 508−516.
    [24]
    Inoue K, Fry EA, Frazier DP. 2016. Transcription factors that interact with p53 and Mdm2. International Journal of Cancer, 138(7): 1577−1585. doi: 10.1002/ijc.29663
    [25]
    Kim R, Emi M, Tanabe K, Murakami S. 2006. Role of the unfolded protein response in cell death. Apoptosis, 11(1): 5−13. doi: 10.1007/s10495-005-3088-0
    [26]
    Koteiche HA, Claxton DP, Mishra S, Stein RA, McDonald ET, Mchaourab HS. 2015. Species-Specific Structural and Functional Divergence of α-Crystallins: Zebrafish αBa- and Rodent αA(ins)-Crystallin Encode Activated Chaperones. Biochemistry, 54(38): 5949−5958. doi: 10.1021/acs.biochem.5b00678
    [27]
    Lee CM, Afshari NA. 2017. The global state of cataract blindness. Current Opinion in Ophthalmology, 28(1): 98−103. doi: 10.1097/ICU.0000000000000340
    [28]
    Lee WS, Yoo WH, Chae HJ. 2015. ER Stress and Autophagy. Current Molecular Medicine, 15(8): 735−745. doi: 10.2174/1566524015666150921105453
    [29]
    Li J, Chen X, Yan Y, Yao K. 2020. Molecular genetics of congenital cataracts. Experimental Eye Research, 191: 107872. doi: 10.1016/j.exer.2019.107872
    [30]
    Li H, Li C, Lu Q, Su T, Ke T, Li DWC, Yuan M, Liu J, Ren X, Zhang Z, Zeng S, Wang QK, Liu M. 2008. Cataract mutation P20S of alphaB-crystallin impairs chaperone activity of alphaA-crystallin and induces apoptosis of human lens epithelial cells. Biochimica Et Biophysica Acta, 1782(5): 303−309. doi: 10.1016/j.bbadis.2008.01.011
    [31]
    Li HS, Zhou YN, Li L, Li SF, Long D, Chen XL, et al. 2019. HIF-1α protects against oxidative stress by directly targeting mitochondria. Redox Biology, 25: 101109. doi: 10.1016/j.redox.2019.101109
    [32]
    Ma J, Yang YR, Chen W, Chen MH, Wang H, Wang XD, et al. 2016. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. Oncology Reports, 36(2): 676−684. doi: 10.3892/or.2016.4860
    [33]
    Malhotra JD, Kaufman RJ. 2007. The endoplasmic reticulum and the unfolded protein response. Seminars in Cell & Developmental Biology, 18(6): 716−731.
    [34]
    Martinez A, Lopez N, Gonzalez C, Hetz C. 2019. Targeting of the unfolded protein response (UPR) as therapy for Parkinson’s disease. Biology of the Cell, 111(6): 161−168. doi: 10.1111/boc.201800068
    [35]
    McManus S, Roux S. 2012. The adaptor protein p62/SQSTM1 in osteoclast signaling pathways. Journal of Molecular Signaling, 7: 1. doi: 10.1186/1750-2187-7-1
    [36]
    Moreau KL, King JA. 2012. Protein misfolding and aggregation in cataract disease and prospects for prevention. Trends in Molecular Medicine, 18(5): 273−282. doi: 10.1016/j.molmed.2012.03.005
    [37]
    Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ. 2009. CHAC1/MGC4504 Is a Novel Proapoptotic Component of the Unfolded Protein Response, Downstream of the ATF4-ATF3-CHOP Cascade. The Journal of Immunology, 182(1): 466−476. doi: 10.4049/jimmunol.182.1.466
    [38]
    Nahomi RB, Wang B, Raghavan CT, Voss O, Doseff AI, Santhoshkumar P, et al. 2013. Chaperone Peptides of α-Crystallin Inhibit Epithelial Cell Apoptosis, Protein Insolubilization, and Opacification in Experimental Cataracts. Journal of Biological Chemistry, 288(18): 13022−13035. doi: 10.1074/jbc.M112.440214
    [39]
    Pendergrass W, Penn P, Possin D, Wolf N. 2005. Accumulation of DNA, Nuclear and Mitochondrial Debris, and ROS at Sites of Age-Related Cortical Cataract in Mice. Investigative Opthalmology & Visual Science, 46(12): 4661.
    [40]
    Roskamp KW, Kozlyuk N, Sengupta S, Bierma JC, Martin RW. 2019. Divalent Cations and the Divergence of βγ-Crystallin Function. Biochemistry, 58(45): 4505−4518. doi: 10.1021/acs.biochem.9b00507
    [41]
    Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I. 2016. The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress. Current Molecular Medicine, 16(6): 533−544. doi: 10.2174/1566524016666160523143937
    [42]
    Shao Y, Wang L, Guo N, Wang S, Yang L, Li Y, et al. 2018. Cas9-nickase–mediated genome editing corrects hereditary tyrosinemia in rats. Journal of Biological Chemistry, 293(18): 6883−6892. doi: 10.1074/jbc.RA117.000347
    [43]
    Sun W, Xiao X, Li S, Guo X, Zhang Q. 2011. Mutation analysis of 12 genes in Chinese families with congenital cataracts. Molecular Vision, 17: 2197−2206.
    [44]
    Tian F, Zhao J, Bu S, Teng H, Yang J, Zhang X, Li X, Dong L. 2020. KLF6 Induces Apoptosis in Human Lens Epithelial Cells Through the ATF4-ATF3-CHOP Axis. Drug Design, Development and Therapy, 14: 1041−1055. doi: 10.2147/DDDT.S218467
    [45]
    Uddin MdS, Tewari D, Sharma G, Kabir MdT, Barreto GE, Bin-Jumah MN, et al. 2020. Molecular Mechanisms of ER Stress and UPR in the Pathogenesis of Alzheimer’s Disease. Molecular Neurobiology, 57(7): 2902−2919. doi: 10.1007/s12035-020-01929-y
    [46]
    Wu SY, Zou P, Mishra S, Mchaourab HS. 2018. Transgenic zebrafish models reveal distinct molecular mechanisms for cataract-linked αA-crystallin mutants. PloS One, 13(11): e0207540. doi: 10.1371/journal.pone.0207540
    [47]
    Xia CH, Liu H, Chang B, Cheng C, Cheung D, Wang M, et al. 2006. Arginine 54 and Tyrosine 118 Residues of αA-Crystallin Are Crucial for Lens Formation and Transparency. Investigative Opthalmology & Visual Science, 47(7): 3004.
    [48]
    Xu J, Wang H, Wang A, Xu J, Fu C, Jia Z, et al. 2021. βB2 W151R mutant is prone to degradation, aggregation and exposes the hydrophobic side chains in the fourth Greek Key motif. Biochimica Et Biophysica Acta. Molecular Basis of Disease, 1867(2): 166018. doi: 10.1016/j.bbadis.2020.166018
    [49]
    Yang J, Liu J, Zhao S, Tian F. 2020a. N6-Methyladenosine METTL3 Modulates the Proliferation and Apoptosis of Lens Epithelial Cells in Diabetic Cataract. Molecular Therapy. Nucleic Acids, 20: 111−116. doi: 10.1016/j.omtn.2020.02.002
    [50]
    Yang X, Xu J, Fu C, Jia Z, Yao K, Chen X. 2020b. The cataract-related S39C variant increases γS-crystallin sensitivity to environmental stress by destroying the intermolecular disulfide cross-links. Biochemical and Biophysical Research Communications, 526(2): 459−465. doi: 10.1016/j.bbrc.2020.03.072
    [51]
    Yang J, Zhou S, Gu J, Wang Y, Guo M, Liu Y. 2015. Differences in Unfolded Protein Response Pathway Activation in the Lenses of Three Types of Cataracts. PloS One, 10(6): e0130705. doi: 10.1371/journal.pone.0130705
    [52]
    Yu Y, Li J, Xu J, Wang Q, Yu Y, Yao K. 2012. Congenital polymorphic cataract associated with a G to A splice site mutation in the human beta-crystallin gene CRYβA3/A1. Molecular Vision, 18: 2213−2220.
    [53]
    Zhou S, Yang J, Wang M, Zheng D, Liu Y. 2020. Endoplasmic reticulum stress regulates epithelial-mesenchymal transition in human lens epithelial cells. Molecular Medicine Reports, 21(1): 173−180.
    [54]
    Zhuang J, Cao Z, Zhu Y, Liu L, Tong Y, Chen X, et al. 2019. Mutation screening of crystallin genes in Chinese families with congenital cataracts. Molecular Vision, 25: 427−437.
  • ZR-2020-354 Supplementary Figures.pdf
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(5)

    Article Metrics

    Article views (1181) PDF downloads(178) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return