GBF1 deficiency causes cataracts in human and mouse.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7613873 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1203 (Electronic) Linking ISSN: 03406717 NLM ISO Abbreviation: Hum Genet Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer-Verlag.

Cataract*/genetics ; Cataract*/pathology ; Autophagy*/genetics ; Unfolded Protein Response*/genetics ; Mice, Knockout* ; Lens, Crystalline*/metabolism ; Lens, Crystalline*/pathology ; X-Box Binding Protein 1*/genetics ; X-Box Binding Protein 1*/metabolism; Animals ; Humans ; Mice ; Female ; Male ; Pedigree ; Mutation

Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bartha I, di Iulio J, Venter JC, Telenti A (2018) Human gene essentiality. Nat Rev Genet 19:51–62. https://doi.org/10.1038/nrg.2017.75. (PMID: 10.1038/nrg.2017.7529082913)
Basu S, Rajakaruna S, Reyes B, Van Bockstaele E, Menko AS (2014) Suppression of MAPK/JNK-MTORC1 signaling leads to premature loss of organelles and nuclei by autophagy during terminal differentiation of lens fiber cells. Autophagy 10:1193–1211. https://doi.org/10.4161/auto.28768. (PMID: 10.4161/auto.28768248133964203547)
Beebe DC (2014) The physiology and pathobiology of the Lens. In: McManus LM, Mitchell RN (eds) Pathobiology of Human Disease. Academic, San Diego, pp 2072–2083. (PMID: 10.1016/B978-0-12-386456-7.04703-1)
Chan WH, Biswas S, Ashworth JL, Lloyd IC (2012) Educational paper. Eur J Pediatrics 171:625–630. https://doi.org/10.1007/s00431-012-1700-1. (PMID: 10.1007/s00431-012-1700-1)
Chen JH, Huang C, Zhang B, Yin S, Liang J, Xu C, Huang Y, Cen LP, Ng TK, Zheng C, Zhang S, Chen H, Pang CP, Zhang M (2016) Mutations of RagA GTPase in mTORC1 pathway are Associated with autosomal Dominant cataracts. PLoS Genet 12:e1006090. https://doi.org/10.1371/journal.pgen.1006090. (PMID: 10.1371/journal.pgen.1006090272942654905677)
Chen J, Wu X, Yao L, Yan L, Zhang L, Qiu J, Liu X, Jia S, Meng A (2017) Impairment of Cargo Transportation caused by gbf1 mutation disrupts Vascular Integrity and causes hemorrhage in zebrafish embryos. J Biol Chem 292:2315–2327. https://doi.org/10.1074/jbc.M116.767608. (PMID: 10.1074/jbc.M116.76760828003365)
Chia J, Wang SC, Wee S, Gill DJ, Tay F, Kannan S, Verma CS, Gunaratne J, Bard FA (2021) Src activates retrograde membrane traffic through phosphorylation of GBF1. Elife 10. https://doi.org/10.7554/eLife.68678.
Citterio C, Vichi A, Pacheco-Rodriguez G, Aponte AM, Moss J, Vaughan M (2008) Unfolded protein response and cell death after depletion of brefeldin A-inhibited guanine nucleotide-exchange protein GBF1. Proc Natl Acad Sci U S A 105:2877–2882. https://doi.org/10.1073/pnas.0712224105. (PMID: 10.1073/pnas.0712224105182870142268553)
García-Mata R, Szul T, Alvarez C, Sztul E (2003) ADP-ribosylation factor/COPI-dependent events at the endoplasmic reticulum-golgi interface are regulated by the guanine nucleotide exchange factor GBF1. Mol Biol Cell 14:2250–2261. https://doi.org/10.1091/mbc.e02-11-0730. (PMID: 10.1091/mbc.e02-11-073012808027194875)
Ibaraki N, Chen SC, Lin LR, Okamoto H, Pipas JM, Reddy VN (1998) Human lens epithelial cell line. Exp Eye Res 67:577–585. https://doi.org/10.1006/exer.1998.0551. (PMID: 10.1006/exer.1998.05519878220)
Ignashkova TI, Gendarme M, Peschk K, Eggenweiler HM, Lindemann RK, Reiling JH (2017) Cell survival and protein secretion associated with Golgi integrity in response to Golgi stress-inducing agents. Traffic 18:530–544. https://doi.org/10.1111/tra.12493. (PMID: 10.1111/tra.1249328485883)
Jiang H, Jiang Q, He Y, Li X, Xu Y, Liu X (2022) XBP1s promotes the development of lung adenocarcinoma via the p–JNK MAPK pathway. Int J Mol Med 49. https://doi.org/10.3892/ijmm.2022.5089.
Kaczmarek B, Verbavatz JM, Jackson CL (2017) GBF1 and Arf1 function in vesicular trafficking, lipid homoeostasis and organelle dynamics. Biol Cell 109:391–399. https://doi.org/10.1111/boc.201700042. (PMID: 10.1111/boc.20170004228985001)
Lenhart PD, Lambert SR (2022) Current management of infantile cataracts. Surv Ophthalmol 67:1476–1505. https://doi.org/10.1016/j.survophthal.2022.03.005. (PMID: 10.1016/j.survophthal.2022.03.0053530732410199332)
Levine B, Kroemer G (2019) Biological functions of Autophagy genes: a Disease Perspective. Cell 176:11–42. https://doi.org/10.1016/j.cell.2018.09.048. (PMID: 10.1016/j.cell.2018.09.048306339016347410)
Li J, Chen X, Yan Y, Yao K (2020) Molecular genetics of congenital cataracts. Exp Eye Res 191:107872. https://doi.org/10.1016/j.exer.2019.107872. (PMID: 10.1016/j.exer.2019.10787231770519)
Liu Z, Huang S, Zheng Y, Zhou T, Hu L, Xiong L, Li DW, Liu Y (2022) The lens epithelium as a major determinant in the development, maintenance, and regeneration of the crystalline lens. Prog Retin Eye Res: 101112. https://doi.org/10.1016/j.preteyeres.2022.101112. (PMID: 10.1016/j.preteyeres.2022.101112)
Lopes-da-Silva M, McCormack JJ, Burden JJ, Harrison-Lavoie KJ, Ferraro F, Cutler DF (2019) A GBF1-Dependent mechanism for environmentally responsive regulation of ER-Golgi transport. Dev Cell 49:786–801e6. https://doi.org/10.1016/j.devcel.2019.04.006. (PMID: 10.1016/j.devcel.2019.04.006310563456764485)
Margariti A, Li H, Chen T, Martin D, Vizcay-Barrena G, Alam S, Karamariti E, Xiao Q, Zampetaki A, Zhang Z, Wang W, Jiang Z, Gao C, Ma B, Chen YG, Cockerill G, Hu Y, Xu Q, Zeng L (2013) XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J Biol Chem 288:859–872. https://doi.org/10.1074/jbc.M112.412783. (PMID: 10.1074/jbc.M112.41278323184933)
Maroofian R, Kaiyrzhanov R, Cali E, Zamani M, Zaki MS, Ferla M, Tortora D, Sadeghian S, Saadi SM, Abdullah U, Karimiani EG, Efthymiou S, Yeşil G, Alavi S, Al Shamsi AM, Tajsharghi H, Abdel-Hamid MS, Saadi NW, Al Mutairi F, Alabdi L, Beetz C, Ali Z, Toosi MB, Rudnik-Schöneborn S, Babaei M, Isohanni P, Muhammad J, Khan S, Al Shalan M, Hickey SE, Marom D, Elhanan E, Kurian MA, Marafi D, Saberi A, Hamid M, Spaull R, Meng L, Lalani S, Maqbool S, Rahman F, Seeger J, Palculict TB, Lau T, Murphy D, Mencacci NE, Steindl K, Begemann A, Rauch A, Akbas S, Aslanger AD, Salpietro V, Yousaf H, Ben-Shachar S, Ejeskär K, Al Aqeel AI, High FA, Armstrong-Javors AE, Zahraei SM, Seifi T, Zeighami J, Shariati G, Sedaghat A, Asl SN, Shahrooei M, Zifarelli G, Burglen L, Ravelli C, Zschocke J, Schatz UA, Ghavideldarestani M, Kamel WA, Van Esch H, Hackenberg A, Taylor JC, Al-Gazali L, Bauer P, Gleeson JJ, Alkuraya FS, Lupski JR, Galehdari H, Azizimalamiri R, Chung WK, Baig SM, Houlden H, Severino M (2023) Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders. Brain 146:5031–5043. https://doi.org/10.1093/brain/awad257. (PMID: 10.1093/brain/awad2573751703510690011)
Mei S, Wu Y, Wang Y, Cui Y, Zhang M, Zhang T, Huang X, Yu S, Yu T, Zhao J (2022) Disruption of PIKFYVE causes congenital cataract in human and zebrafish. Elife 11. https://doi.org/10.7554/eLife.71256. (PMID: 10.7554/eLife.71256)
Morishita H, Mizushima N (2016) Autophagy in the lens. Exp Eye Res 144:22–28. https://doi.org/10.1016/j.exer.2015.08.019. (PMID: 10.1016/j.exer.2015.08.01926302409)
Morishita H, Eguchi S, Kimura H, Sasaki J, Sakamaki Y, Robinson ML, Sasaki T, Mizushima N (2013) Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J Biol Chem 288:11436–11447. https://doi.org/10.1074/jbc.M112.437103. (PMID: 10.1074/jbc.M112.437103234797323630873)
Motulsky HJ (2016) GraphPad Statistics Guide. http://www.graphpad.com/guides/prism/10/statistics/index.htm.
Pankiv S, Alemu EA, Brech A, Bruun JA, Lamark T, Overvatn A, Bjørkøy G, Johansen T (2010) FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J Cell Biol 188:253–269. https://doi.org/10.1083/jcb.200907015. (PMID: 10.1083/jcb.200907015201009112812517)
Parzych KR, Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20:460–473. https://doi.org/10.1089/ars.2013.5371. (PMID: 10.1089/ars.2013.5371237252953894687)
Ping X, Liang J, Shi K, Bao J, Wu J, Yu X, Tang X, Zou J, Shentu X (2021) Rapamycin relieves the cataract caused by ablation of Gja8b through stimulating autophagy in zebrafish. Autophagy 17:3323–3337. https://doi.org/10.1080/15548627.2021.1872188. (PMID: 10.1080/15548627.2021.1872188334724938632074)
Sagona AP, Nezis IP, Stenmark H (2014) Association of CHMP4B and autophagy with micronuclei: implications for cataract formation. Biomed Res Int 2014:974393. https://doi.org/10.1155/2014/974393. (PMID: 10.1155/2014/974393247415673967805)
Selyunin AS, Iles LR, Bartholomeusz G, Mukhopadhyay S (2017) Genome-wide siRNA screen identifies UNC50 as a regulator of Shiga toxin 2 trafficking. J Cell Biol 216:3249–3262. https://doi.org/10.1083/jcb.201704015. (PMID: 10.1083/jcb.201704015288830405626549)
Shiels A, Hejtmancik JF (2019) Biology of inherited cataracts and opportunities for treatment. Annu Rev Vis Sci 5:123–149. https://doi.org/10.1146/annurev-vision-091517-034346. (PMID: 10.1146/annurev-vision-091517-034346315251396791712)
Shiels A, Hejtmancik JF (2021) Inherited cataracts: genetic mechanisms and pathways new and old. Exp Eye Res 209:108662. https://doi.org/10.1016/j.exer.2021.108662. (PMID: 10.1016/j.exer.2021.108662341260808595562)
Tu C, Li H, Liu X, Wang Y, Li W, Meng L, Wang W, Li Y, Li D, Du J, Lu G, Lin G, Tan YQ (2021) TDRD7 participates in lens development and spermiogenesis by mediating autophagosome maturation. Autophagy 17:3848–3864. https://doi.org/10.1080/15548627.2021.1894058. (PMID: 10.1080/15548627.2021.1894058336186328632297)
Wang Q, Wang D, Qin T, Zhang X, Lin X, Chen J, Chen W, Zhao L, Huang W, Lin Z, Li J, Dongye M, Wu X, Wang X, Li X, Lin Y, Tan H, Liu Y, Lin H, Chen W (2024) Early diagnosis of syndromic congenital cataracts in a large cohort of congenital cataracts. Am J Ophthalmol 263:206–213. https://doi.org/10.1016/j.ajo.2023.10.022. (PMID: 10.1016/j.ajo.2023.10.02238184101)
Wen C, Zhou Y, Xu Y, Tan H, Pang C, Liu H, Liu K, Wei L, Luo H, Qin T, He C, Liu C, Zhou C (2021) The Regulatory Role of GBF1 on Osteoclast activation through EIF2a mediated ER stress and novel marker FAM129A induction. Front Cell Dev Biol 9:706768. https://doi.org/10.3389/fcell.2021.706768. (PMID: 10.3389/fcell.2021.706768345138388424197)
Wignes JA, Goldman JW, Weihl CC, Bartley MG, Andley UP (2013) p62 expression and autophagy in αB-crystallin R120G mutant knock-in mouse model of hereditary cataract. Exp Eye Res 115:263–273. https://doi.org/10.1016/j.exer.2013.06.026. (PMID: 10.1016/j.exer.2013.06.02623872361)
Xu P, Das M, Reilly J, Davis RJ (2011) JNK regulates FoxO-dependent autophagy in neurons. Genes Dev 25:310–322. https://doi.org/10.1101/gad.1984311. (PMID: 10.1101/gad.1984311213251323042155)
Zhao L, Chen XJ, Zhu J, Xi YB, Yang X, Hu LD, Ouyang H, Patel SH, Jin X, Lin D, Wu F, Flagg K, Cai H, Li G, Cao G, Lin Y, Chen D, Wen C, Chung C, Wang Y, Qiu A, Yeh E, Wang W, Hu X, Grob S, Abagyan R, Su Z, Tjondro HC, Zhao XJ, Luo H, Hou R, Jefferson J, Perry P, Gao W, Kozak I, Granet D, Li Y, Sun X, Wang J, Zhang L, Liu Y, Yan YB, Zhang K (2015) Lanosterol reverses protein aggregation in cataracts. Nature 523:607–611. https://doi.org/10.1038/nature14650. (PMID: 10.1038/nature1465026200341)
Zhou YY, Li Y, Jiang WQ, Zhou LF (2015) MAPK/JNK signalling: a potential autophagy regulation pathway. Biosci Rep 35. https://doi.org/10.1042/bsr20140141.
Zou YJ, Shan MM, Pan ZN, Pan MH, Li XH, Sun SC (2021) Loss of Arf Guanine Nucleotide Exchange factor GBF1 activity disturbs Organelle Dynamics in Mouse oocytes. Microsc Microanal 27:400–408. https://doi.org/10.1017/s1431927620024885. (PMID: 10.1017/s143192762002488533478608)

HUST: 2019JYCXJJ035 Fundamental Research Funds for the Central Universities; 2023YFC2706300 National Key R&D Program of China; 81870959 National Natural Science Foundation of China; 2016QYTD02 Program for HUST Academic Frontier Youth Team

0 (X-Box Binding Protein 1)

Date Created: 20240807 Date Completed: 20241029 Latest Revision: 20241029

20241031

10.1007/s00439-024-02697-8

39110251