Cataract-causing Allele in CRYAA (Y118D) Proceeds Through Endoplasmic Reticulum Stress in Mouse Model

Overview

Journal Zool Res

Publisher Science Press

Specialties Biology
Veterinary Medicine

Date 2021 Apr 30

PMID 33929105

Citations 6

Authors

Zhe-Kun Jia

Chen-Xi Fu

Ai-Ling Wang

Ke Yao

Xiang-Jun Chen

Affiliations

Soon will be listed here.

Abstract

As small heat shock proteins, α-crystallins function as molecular chaperones and inhibit the misfolding and aggregation of β/γ-crystallins. Genetic mutations of 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.

Citing Articles

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References

Malhotra J, Kaufman R . The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol. 2007; 18(6):716-31. PMC: 2706143. DOI: 10.1016/j.semcdb.2007.09.003. View

Xu J, Wang H, Wang A, Xu J, Fu C, Jia Z . βB2 W151R mutant is prone to degradation, aggregation and exposes the hydrophobic side chains in the fourth Greek Key motif. Biochim Biophys Acta Mol Basis Dis. 2020; 1867(2):166018. DOI: 10.1016/j.bbadis.2020.166018. View

Hejtmancik J . Congenital cataracts and their molecular genetics. Semin Cell Dev Biol. 2007; 19(2):134-49. PMC: 2288487. DOI: 10.1016/j.semcdb.2007.10.003. View

Crawford R, Prescott E, Sylvester C, Higdon A, Shan J, Kilberg M . Human CHAC1 Protein Degrades Glutathione, and mRNA Induction Is Regulated by the Transcription Factors ATF4 and ATF3 and a Bipartite ATF/CRE Regulatory Element. J Biol Chem. 2015; 290(25):15878-15891. PMC: 4505494. DOI: 10.1074/jbc.M114.635144. View

Shao Y, Wang L, Guo N, Wang S, Yang L, Li Y . Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats. J Biol Chem. 2018; 293(18):6883-6892. PMC: 5936814. DOI: 10.1074/jbc.RA117.000347. View

Li J, Chen X, Yan Y, Yao K . Molecular genetics of congenital cataracts. Exp Eye Res. 2019; 191:107872. DOI: 10.1016/j.exer.2019.107872. View

Frankfater C, Bozeman S, Hsu F, Andley U . Alpha-crystallin mutations alter lens metabolites in mouse models of human cataracts. PLoS One. 2020; 15(8):e0238081. PMC: 7446835. DOI: 10.1371/journal.pone.0238081. View

Yang J, Liu J, Zhao S, Tian F . N-Methyladenosine METTL3 Modulates the Proliferation and Apoptosis of Lens Epithelial Cells in Diabetic Cataract. Mol Ther Nucleic Acids. 2020; 20:111-116. PMC: 7066033. DOI: 10.1016/j.omtn.2020.02.002. View

Lee W, Yoo W, Chae H . ER Stress and Autophagy. Curr Mol Med. 2015; 15(8):735-45. DOI: 10.2174/1566524015666150921105453. View

10.

Fusakio M, Willy J, Wang Y, Mirek E, Al Baghdadi R, Adams C . Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol Biol Cell. 2016; 27(9):1536-51. PMC: 4850040. DOI: 10.1091/mbc.E16-01-0039. View

11.

Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl J, Majsterek I . The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress. Curr Mol Med. 2016; 16(6):533-44. PMC: 5008685. DOI: 10.2174/1566524016666160523143937. View

12.

Cheng C, Xia C, Huang Q, Ding L, Horwitz J, Gong X . Altered chaperone-like activity of alpha-crystallins promotes cataractogenesis. J Biol Chem. 2010; 285(52):41187-93. PMC: 3003416. DOI: 10.1074/jbc.M110.154534. View

13.

Kim R, Emi M, Tanabe K, Murakami S . Role of the unfolded protein response in cell death. Apoptosis. 2005; 11(1):5-13. DOI: 10.1007/s10495-005-3088-0. View

14.

Martinez A, Lopez N, Gonzalez C, Hetz C . Targeting of the unfolded protein response (UPR) as therapy for Parkinson's disease. Biol Cell. 2019; 111(6):161-168. DOI: 10.1111/boc.201800068. View

15.

Mungrue I, Pagnon J, Kohannim O, Gargalovic P, Lusis A . CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J Immunol. 2008; 182(1):466-76. PMC: 2846782. DOI: 10.4049/jimmunol.182.1.466. View

16.

Sun W, Xiao X, Li S, Guo X, Zhang Q . Mutation analysis of 12 genes in Chinese families with congenital cataracts. Mol Vis. 2011; 17:2197-206. PMC: 3159683. View

17.

Wu S, Zou P, Mishra S, Mchaourab H . Transgenic zebrafish models reveal distinct molecular mechanisms for cataract-linked αA-crystallin mutants. PLoS One. 2018; 13(11):e0207540. PMC: 6261105. DOI: 10.1371/journal.pone.0207540. View

18.

Chothe P, Thakkar S, Gnana-Prakasam J, Ananth S, Hinton D, Kannan R . Identification of a novel sodium-coupled oligopeptide transporter (SOPT2) in mouse and human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2009; 51(1):413-20. PMC: 3973186. DOI: 10.1167/iovs.09-4048. View

19.

Delaye M, Tardieu A . Short-range order of crystallin proteins accounts for eye lens transparency. Nature. 1983; 302(5907):415-7. DOI: 10.1038/302415a0. View

20.

Yang X, Xu J, Fu C, Jia Z, Yao K, Chen X . The cataract-related S39C variant increases γS-crystallin sensitivity to environmental stress by destroying the intermolecular disulfide cross-links. Biochem Biophys Res Commun. 2020; 526(2):459-465. DOI: 10.1016/j.bbrc.2020.03.072. View