Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration
Autoři:
Passley Hargrove-Grimes aff001; Anupam K. Mondal aff001; Jessica Gumerson aff001; Jacob Nellissery aff001; Angel M. Aponte aff003; Linn Gieser aff001; Haohua Qian aff004; Robert N. Fariss aff005; Juan S. Bonifacino aff006; Tiansen Li aff001; Anand Swaroop aff001
Působiště autorů:
Neurobiology, Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America
aff001; Institute of Biomedical Sciences, George Washington University, Washington, District of Columbia, United States of America
aff002; Proteomics Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America
aff003; Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America
aff004; Biological Imaging Core, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America
aff005; Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute for Child Health and Development, National Institutes of Health, Bethesda, Maryland, United States of America
aff006
Vyšlo v časopise:
Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration. PLoS Genet 16(12): e1009259. doi:10.1371/journal.pgen.1009259
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009259
Souhrn
Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling and degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding the protein RabGEF1 or Rabex-5) as the only gene associated with Rab GTPases that exhibited strong concordance with retinal photoreceptor differentiation. Loss of Rabgef1 in mice (Rabgef1-/-) resulted in defects specifically of photoreceptor morphology and almost complete loss of both rod and cone function as early as eye opening; however, aberrant outer segment formation could only partly account for visual function deficits. RabGEF1 protein in retinal photoreceptors interacts with Rabaptin-5, and RabGEF1 absence leads to reduction of early endosomes consistent with studies in other mammalian cells and tissues. Electron microscopy analyses reveal abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles and enhanced immunostaining for LC3A/B and p62 in Rabgef1-/- photoreceptors, consistent with compromised autophagy. Transcriptome analysis of the developing Rabgef1-/- retina reveals altered expression of 2469 genes related to multiple pathways including phototransduction, mitochondria, oxidative stress and endocytosis, suggesting an early trajectory of photoreceptor cell death. Our results implicate an essential role of the RabGEF1-modulated endocytic and autophagic pathways in photoreceptor differentiation and homeostasis. We propose that RabGEF1 and associated components are potential candidates for syndromic traits that include a retinopathy phenotype.
Klíčová slova:
Autophagic cell death – Endocytosis – Eyes – Immunostaining – Photoreceptors – Phototransduction – Retina – Vision
Zdroje
1. Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet. 2010;11(4):273–84. Epub 2010/03/10. doi: 10.1038/nrg2717 20212494.
2. Broadgate S, Yu J, Downes SM, Halford S. Unravelling the genetics of inherited retinal dystrophies: Past, present and future. Prog Retin Eye Res. 2017;59:53–96. Epub 2017/04/02. doi: 10.1016/j.preteyeres.2017.03.003 28363849.
3. Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018;66:157–86. Epub 2018/03/30. doi: 10.1016/j.preteyeres.2018.03.005 29597005.
4. Lamb TD, Collin SP, Pugh EN Jr. Evolution of the vertebrate eye: opsins, photoreceptors, retina and eye cup. Nat Rev Neurosci. 2007;8(12):960–76. Epub 2007/11/21. doi: 10.1038/nrn2283 18026166; PubMed Central PMCID: PMC3143066.
5. May-Simera H, Nagel-Wolfrum K, Wolfrum U. Cilia—The sensory antennae in the eye. Prog Retin Eye Res. 2017;60:144–80. Epub 2017/05/16. doi: 10.1016/j.preteyeres.2017.05.001 28504201.
6. Swaroop A, Kim D, Forrest D. Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci. 2010;11(8):563–76. Epub 2010/07/22. doi: 10.1038/nrn2880 20648062.
7. Brzezinski JA, Reh TA. Photoreceptor cell fate specification in vertebrates. Development. 2015;142(19):3263–73. Epub 2015/10/08. doi: 10.1242/dev.127043 26443631; PubMed Central PMCID: PMC4631758.
8. Pearring JN, Salinas RY, Baker SA, Arshavsky VY. Protein sorting, targeting and trafficking in photoreceptor cells. Prog Retin Eye Res. 2013;36:24–51. Epub 2013/04/09. doi: 10.1016/j.preteyeres.2013.03.002 23562855; PubMed Central PMCID: PMC3759535.
9. Estrada-Cuzcano A, Roepman R, Cremers FP, den Hollander AI, Mans DA. Non-syndromic retinal ciliopathies: translating gene discovery into therapy. Human molecular genetics. 2012;21(R1):R111–24. doi: 10.1093/hmg/dds298 22843501.
10. Rachel RA, Li T, Swaroop A. Photoreceptor sensory cilia and ciliopathies: focus on CEP290, RPGR and their interacting proteins. Cilia. 2012;1(1):22. Epub 2013/01/29. doi: 10.1186/2046-2530-1-22 23351659; PubMed Central PMCID: PMC3563624.
11. Bujakowska KM, Liu Q, Pierce EA. Photoreceptor Cilia and Retinal Ciliopathies. Cold Spring Harb Perspect Biol. 2017;9(10). Epub 2017/03/16. doi: 10.1101/cshperspect.a028274 28289063.
12. Bachmann-Gagescu R, Neuhauss SC. The photoreceptor cilium and its diseases. Curr Opin Genet Dev. 2019;56:22–33. Epub 2019/07/02. doi: 10.1016/j.gde.2019.05.004 31260874.
13. Schmid SL, Sorkin A, Zerial M. Endocytosis: Past, present, and future. Cold Spring Harb Perspect Biol. 2014;6(12):a022509. Epub 2014/11/02. doi: 10.1101/cshperspect.a022509 25359499; PubMed Central PMCID: PMC4292149.
14. Jovic M, Sharma M, Rahajeng J, Caplan S. The early endosome: a busy sorting station for proteins at the crossroads. Histol Histopathol. 2010;25(1):99–112. Epub 2009/11/20. doi: 10.14670/HH-25.99 19924646; PubMed Central PMCID: PMC2810677.
15. Grant BD, Donaldson JG. Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol. 2009;10(9):597–608. Epub 2009/08/22. doi: 10.1038/nrm2755 19696797; PubMed Central PMCID: PMC3038567.
16. Tooze SA, Abada A, Elazar Z. Endocytosis and autophagy: exploitation or cooperation? Cold Spring Harb Perspect Biol. 2014;6(5):a018358. Epub 2014/05/03. doi: 10.1101/cshperspect.a018358 24789822; PubMed Central PMCID: PMC3996471.
17. Wandinger-Ness A, Zerial M. Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harb Perspect Biol. 2014;6(11):a022616. Epub 2014/10/25. doi: 10.1101/cshperspect.a022616 25341920; PubMed Central PMCID: PMC4413231.
18. Muller MP, Goody RS. Molecular control of Rab activity by GEFs, GAPs and GDI. Small GTPases. 2018;9(1–2):5–21. Epub 2017/01/06. doi: 10.1080/21541248.2016.1276999 28055292; PubMed Central PMCID: PMC5902221.
19. Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10(8):513–25. Epub 2009/07/16. doi: 10.1038/nrm2728 19603039.
20. Galvez T, Gilleron J, Zerial M, O'Sullivan GA. SnapShot: Mammalian Rab proteins in endocytic trafficking. Cell. 2012;151(1):234–e2. Epub 2012/10/02. doi: 10.1016/j.cell.2012.09.013 23021225.
21. Seixas E, Barros M, Seabra MC, Barral DC. Rab and Arf proteins in genetic diseases. Traffic. 2013;14(8):871–85. Epub 2013/04/10. doi: 10.1111/tra.12072 23565987.
22. D'Adamo P, Masetti M, Bianchi V, More L, Mignogna ML, Giannandrea M, et al. RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions. Neurosci Biobehav Rev. 2014;46 Pt 2:302–14. Epub 2014/01/15. doi: 10.1016/j.neubiorev.2013.12.009 24412241.
23. Seabra MC, Ho YK, Anant JS. Deficient geranylgeranylation of Ram/Rab27 in choroideremia. The Journal of biological chemistry. 1995;270(41):24420–7. Epub 1995/10/13. doi: 10.1074/jbc.270.41.24420 7592656.
24. Roosing S, Rohrschneider K, Beryozkin A, Sharon D, Weisschuh N, Staller J, et al. Mutations in RAB28, Encoding a Farnesylated Small GTPase, Are Associated with Autosomal-Recessive Cone-Rod Dystrophy. American journal of human genetics. 2013;93(1):110–7. doi: 10.1016/j.ajhg.2013.05.005 23746546; PubMed Central PMCID: PMC3710761.
25. Lumb JH, Leung KF, Dubois KN, Field MC. Rab28 function in trypanosomes: interactions with retromer and ESCRT pathways. Journal of cell science. 2011;124(Pt 22):3771–83. Epub 2011/11/22. doi: 10.1242/jcs.079178 22100919; PubMed Central PMCID: PMC3225266.
26. Hollyfield JG, Rayborn ME. Endocytosis in the inner segment of rod photoreceptors: analysis of Xenopus laevis retinas using horseradish peroxidase. Experimental eye research. 1987;45(5):703–19. Epub 1987/11/01. doi: 10.1016/s0014-4835(87)80119-7 3428395.
27. Van Hook MJ, Thoreson WB. Rapid synaptic vesicle endocytosis in cone photoreceptors of salamander retina. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2012;32(50):18112–23. Epub 2012/12/15. doi: 10.1523/JNEUROSCI.1764-12.2012 23238726; PubMed Central PMCID: PMC3547361.
28. Pinal N, Pichaud F. Dynamin- and Rab5-dependent endocytosis is required to prevent Drosophila photoreceptor degeneration. Journal of cell science. 2011;124(Pt 9):1564–70. Epub 2011/04/14. doi: 10.1242/jcs.082115 21486953; PubMed Central PMCID: PMC3078820.
29. Hoshino A, Ratnapriya R, Brooks MJ, Chaitankar V, Wilken MS, Zhang C, et al. Molecular Anatomy of the Developing Human Retina. Developmental cell. 2017;43:763–79. Epub 2017/12/14. doi: 10.1016/j.devcel.2017.10.029 29233477.
30. Brooks MJ, Chen HY, Kelley RA, Mondal AK, Nagashima K, De Val N, et al. Improved Retinal Organoid Differentiation by Modulating Signaling Pathways Revealed by Comparative Transcriptome Analyses with Development In Vivo. Stem cell reports. 2019;13(5):891–905. Epub 2019/10/22. doi: 10.1016/j.stemcr.2019.09.009 31631019; PubMed Central PMCID: PMC6895716.
31. Stenmark H, Vitale G, Ullrich O, Zerial M. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell. 1995;83(3):423–32. Epub 1995/11/03. doi: 10.1016/0092-8674(95)90120-5 8521472.
32. Horiuchi H, Lippe R, McBride HM, Rubino M, Woodman P, Stenmark H, et al. A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links nucleotide exchange to effector recruitment and function. Cell. 1997;90(6):1149–59. Epub 1997/10/10. doi: 10.1016/s0092-8674(00)80380-3 9323142.
33. Zhang Z, Zhang T, Wang S, Gong Z, Tang C, Chen J, et al. Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5. eLife. 2014;3. Epub 2014/06/25. doi: 10.7554/eLife.02687 24957337; PubMed Central PMCID: PMC4102244.
34. Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B, et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell. 1992;70(5):715–28. Epub 1992/09/04. doi: 10.1016/0092-8674(92)90306-w 1516130.
35. Carter-Dawson LD, LaVail MM. Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine. J Comp Neurol. 1979;188(2):263–72. Epub 1979/11/15. doi: 10.1002/cne.901880205 500859.
36. Kim JW, Yang HJ, Brooks MJ, Zelinger L, Karakulah G, Gotoh N, et al. NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors. Cell reports. 2016;17(9):2460–73. Epub 2016/11/24. doi: 10.1016/j.celrep.2016.10.074 27880916; PubMed Central PMCID: PMC5131731.
37. Tam SY, Tsai M, Snouwaert JN, Kalesnikoff J, Scherrer D, Nakae S, et al. RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nat Immunol. 2004;5(8):844–52. Epub 2004/07/06. doi: 10.1038/ni1093 15235600.
38. Simonsen A, Lippe R, Christoforidis S, Gaullier JM, Brech A, Callaghan J, et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature. 1998;394(6692):494–8. Epub 1998/08/11. doi: 10.1038/28879 9697774.
39. Zhou F, Zou S, Chen Y, Lipatova Z, Sun D, Zhu X, et al. A Rab5 GTPase module is important for autophagosome closure. PLoS genetics. 2017;13(9):e1007020. Epub 2017/09/22. doi: 10.1371/journal.pgen.1007020 28934205; PubMed Central PMCID: PMC5626503.
40. Yamano K, Wang C, Sarraf SA, Munch C, Kikuchi R, Noda NN, et al. Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife. 2018;7. Epub 2018/01/24. doi: 10.7554/eLife.31326 29360040; PubMed Central PMCID: PMC5780041.
41. Zeigerer A, Gilleron J, Bogorad RL, Marsico G, Nonaka H, Seifert S, et al. Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature. 2012;485(7399):465–70. Epub 2012/05/25. doi: 10.1038/nature11133 22622570.
42. Mattera R, Tsai YC, Weissman AM, Bonifacino JS. The Rab5 guanine nucleotide exchange factor Rabex-5 binds ubiquitin (Ub) and functions as a Ub ligase through an atypical Ub-interacting motif and a zinc finger domain. The Journal of biological chemistry. 2006;281(10):6874–83. Epub 2006/01/13. doi: 10.1074/jbc.M509939200 16407276.
43. Mattera R, Bonifacino JS. Ubiquitin binding and conjugation regulate the recruitment of Rabex-5 to early endosomes. The EMBO journal. 2008;27(19):2484–94. Epub 2008/09/06. doi: 10.1038/emboj.2008.177 18772883; PubMed Central PMCID: PMC2567407.
44. Carney DS, Davies BA, Horazdovsky BF. Vps9 domain-containing proteins: activators of Rab5 GTPases from yeast to neurons. Trends Cell Biol. 2006;16(1):27–35. Epub 2005/12/07. doi: 10.1016/j.tcb.2005.11.001 16330212.
45. Marichal T, Gaudenzio N, El Abbas S, Sibilano R, Zurek O, Starkl P, et al. Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis. The Journal of clinical investigation. 2016;126(12):4497–515. Epub 2016/11/08. doi: 10.1172/JCI86359 27820702; PubMed Central PMCID: PMC5127679.
46. Sudhof TC. The synaptic vesicle cycle. Annual review of neuroscience. 2004;27:509–47. Epub 2004/06/26. doi: 10.1146/annurev.neuro.26.041002.131412 15217342.
47. Mahapatra KK, Panigrahi DP, Praharaj PP, Bhol CS, Patra S, Mishra SR, et al. Molecular interplay of autophagy and endocytosis in human health and diseases. Biological reviews of the Cambridge Philosophical Society. 2019;94(4):1576–90. Epub 2019/04/17. doi: 10.1111/brv.12515 30989802.
48. Birgisdottir AB, Johansen T. Autophagy and endocytosis—interconnections and interdependencies. Journal of cell science. 2020;133(10). Epub 2020/06/06. doi: 10.1242/jcs.228114 32501285.
49. Ravikumar B, Imarisio S, Sarkar S, O'Kane CJ, Rubinsztein DC. Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. Journal of cell science. 2008;121(Pt 10):1649–60. Epub 2008/04/24. doi: 10.1242/jcs.025726 18430781; PubMed Central PMCID: PMC2635563.
50. Heckmann BL, Teubner BJW, Tummers B, Boada-Romero E, Harris L, Yang M, et al. LC3-Associated Endocytosis Facilitates beta-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease. Cell. 2019;178(3):536–51 e14. Epub 2019/07/02. doi: 10.1016/j.cell.2019.05.056 31257024; PubMed Central PMCID: PMC6689199.
51. Dwivedi M, Sung H, Shen H, Park BJ, Lee S. Disruption of endocytic pathway regulatory genes activates autophagy in C. elegans. Mol Cells. 2011;31(5):477–81. Epub 2011/05/28. doi: 10.1007/s10059-011-1035-1 21618079; PubMed Central PMCID: PMC3887608.
52. Szatmari Z, Sass M. The autophagic roles of Rab small GTPases and their upstream regulators: a review. Autophagy. 2014;10(7):1154–66. Epub 2014/06/11. doi: 10.4161/auto.29395 24915298; PubMed Central PMCID: PMC4203544.
53. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8(4):445–544. Epub 2012/09/12. doi: 10.4161/auto.19496 22966490; PubMed Central PMCID: PMC3404883.
54. von Eisenhart-Rothe P, Grubman A, Greferath U, Fothergill LJ, Jobling AI, Phipps JA, et al. Failure of Autophagy-Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed in Cln6nclf Mice. Investigative ophthalmology & visual science. 2018;59(12):5082–97. Epub 2018/10/30. doi: 10.1167/iovs.18-24757 30372735.
55. Campla CK, Mast H, Dong L, Lei J, Halford S, Sekaran S, et al. Targeted deletion of an NRL- and CRX-regulated alternative promoter specifically silences FERM and PDZ domain containing 1 (Frmpd1) in rod photoreceptors. Human molecular genetics. 2019;28(5):804–17. Epub 2018/11/18. doi: 10.1093/hmg/ddy388 30445545; PubMed Central PMCID: PMC6381315.
56. Stromhaug PE, Berg TO, Fengsrud M, Seglen PO. Purification and characterization of autophagosomes from rat hepatocytes. The Biochemical journal. 1998;335 (Pt 2):217–24. Epub 1998/10/08. doi: 10.1042/bj3350217 9761717; PubMed Central PMCID: PMC1219772.
57. Stoehr A, Yang Y, Patel S, Evangelista AM, Aponte A, Wang G, et al. Prolyl hydroxylation regulates protein degradation, synthesis, and splicing in human induced pluripotent stem cell-derived cardiomyocytes. Cardiovasc Res. 2016;110(3):346–58. Epub 2016/04/21. doi: 10.1093/cvr/cvw081 27095734; PubMed Central PMCID: PMC4872881.
58. Elias JE, Gygi SP. Target-decoy search strategy for mass spectrometry-based proteomics. Methods Mol Biol. 2010;604:55–71. Epub 2009/12/17. doi: 10.1007/978-1-60761-444-9_5 20013364; PubMed Central PMCID: PMC2922680.
59. Roger JE, Hiriyanna A, Gotoh N, Hao H, Cheng DF, Ratnapriya R, et al. OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness. The Journal of clinical investigation. 2014;124(2):631–43. Epub 2014/01/03. doi: 10.1172/JCI72722 24382353; PubMed Central PMCID: PMC3904630.
60. Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47(W1):W191–W8. Epub 2019/05/09. doi: 10.1093/nar/gkz369 31066453; PubMed Central PMCID: PMC6602461.
61. Sergushichev AA, Loboda AA, Jha AK, Vincent EE, Driggers EM, Jones RG, et al. GAM: a web-service for integrated transcriptional and metabolic network analysis. Nucleic Acids Res. 2016;44(W1):W194–200. Epub 2016/04/22. doi: 10.1093/nar/gkw266 27098040; PubMed Central PMCID: PMC4987878.
62. Herwig R, Hardt C, Lienhard M, Kamburov A. Analyzing and interpreting genome data at the network level with ConsensusPathDB. Nat Protoc. 2016;11(10):1889–907. Epub 2016/09/09. doi: 10.1038/nprot.2016.117 27606777.
63. Akimoto M, Cheng H, Zhu D, Brzezinski JA, Khanna R, Filippova E, et al. Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(10):3890–5. Epub 2006/03/01. 0508214103 [pii] doi: 10.1073/pnas.0508214103 16505381.
64. Calvo SE, Clauser KR, Mootha VK. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 2016;44(D1):D1251–7. Epub 2015/10/10. doi: 10.1093/nar/gkv1003 26450961; PubMed Central PMCID: PMC4702768.
65. Walker SA, Ktistakis NT. Autophagosome Biogenesis Machinery. Journal of molecular biology. 2020;432(8):2449–61. Epub 2019/11/11. doi: 10.1016/j.jmb.2019.10.027 31705882.
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