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By the Tips of Your Cilia: Ciliogenesis in the Retina and the Ubiquitin-Proteasome System

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Proteostasis and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1233))

Abstract

Primary cilia are microtubule-based sensory organelles that are involved in the organization of numerous key signals during development and in differentiated tissue homeostasis. In fact, the formation and resorption of cilia highly depends on the cell cycle phase in replicative cells, and the ubiquitin proteasome pathway (UPS) proteins, such as E3 ligases and deubiquitinating enzymes, promote microtubule assembly and disassembly by regulating the degradation/availability of ciliary regulatory proteins. Also, many differentiated tissues display cilia, and mutations in genes encoding ciliary proteins are associated with several human pathologies, named ciliopathies, which are multi-organ rare diseases. The retina is one of the organs most affected by ciliary gene mutations because photoreceptors are ciliated cells. Photoreception and phototransduction occur in the outer segment, a highly specialized neurosensory cilium. In this review, we focus on the function of UPS proteins in ciliogenesis and cilia length control in replicative cells and compare it with the scanty data on the identified UPS genes that cause syndromic and non-syndromic inherited retinal disorders. Clearly, further work using animal models and gene-edited mutants of ciliary genes in cells and organoids will widen the landscape of UPS involvement in ciliogenesis and cilia homeostasis.

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References

  1. Hoon M, Okawa H, Della Santina L, Wong ROL (2014) Functional architecture of the retina: development and disease. Prog Retin Eye Res 42:44–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. den Hollander AI, Black A, Bennett J, Cremers FPM (2010) Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies. J Clin Invest 120:3042–3053

    Article  CAS  Google Scholar 

  3. Swaroop A, Kim D, Forrest D (2010) Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci 11:563–576

    Article  CAS  PubMed  Google Scholar 

  4. Khanna H (2015) Photoreceptor sensory cilium: traversing the ciliary gate. Cell 4:674–686

    Article  CAS  Google Scholar 

  5. Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881

    Article  CAS  PubMed  Google Scholar 

  6. Sparrow JR, Hicks D, Hamel CP (2010) The retinal pigment epithelium in health and disease. Curr Mol Med 10:802–823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS (2010) Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet 11:273–284

    Article  CAS  PubMed  Google Scholar 

  8. Fliegauf M, Benzing T, Omran H (2007) When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8:880–893

    Article  CAS  PubMed  Google Scholar 

  9. Hildebrandt F, Benzing T, Katsanis N (2011) Ciliopathies. N Engl J Med 364:1533–1543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gerdes JM, Davis EE, Katsanis N (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137:32–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rosenbaum JL, Witman GB (2002) Intraflagellar transport. Nat Rev Mol Cell Biol 3:813–825

    Article  CAS  PubMed  Google Scholar 

  12. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479

    Article  CAS  PubMed  Google Scholar 

  13. Hochstrasser M (1996) Ubiquitin-dependent protein degradation. Annu Rev Genet 30:405–439

    Article  CAS  PubMed  Google Scholar 

  14. Senft D, Qi J, Ronai ZA (2018) Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18:69–88

    Article  CAS  PubMed  Google Scholar 

  15. Clague JM, Barsukov I, Coulson MJ et al (2013) Deubiquitylases from genes to organism. Physiol Rev 93:1289–1315

    Article  CAS  PubMed  Google Scholar 

  16. Kirkin V, Dikic I (2007) Role of ubiquitin- and Ubl-binding proteins in cell signaling. Curr Opin Cell Biol 19:199–205

    Article  CAS  PubMed  Google Scholar 

  17. Onishi A, Peng G-H, Hsu C et al (2009) Pias3-dependent SUMOylation directs rod photoreceptor development. Neuron 61:234–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Abad-Morales V, Domènech EB, Garanto A, Marfany G (2015) mRNA expression analysis of the SUMO pathway genes in the adult mouse retina. Biol Open 4:224–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Esquerdo M, Grau-Bové X, Garanto A et al (2016) Expression atlas of the deubiquitinating enzymes in the adult mouse retina, their evolutionary diversification and phenotypic roles. PLoS One 11:e0150364

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Malicki JJ, Johnson CA (2017) The cilium: cellular antenna and central processing unit. Trends Cell Biol 27:126–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mick DU, Rodrigues RB, Leib RD, Adams CM, Chien AS, Gygi SP, Nachury MV (2015) Proteomics of primary cilia by proximity labeling. Dev Cell 35:497–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim J, Lee JE, Heynen-Genel S et al (2010) Functional genomic screen for modulators of ciliogenesis and cilium length. Nature 464:1048–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Villumsen BH, Danielsen JR, Povlsen L et al (2013) A new cellular stress response that triggers centriolar satellite reorganization and ciliogenesis. EMBO J 32:3029–3040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hossain D, Tsang WY (2018) The role of ubiquitination in the regulation of primary cilia assembly and disassembly. Semin Cell Dev Biol 93:145–152

    Article  PubMed  CAS  Google Scholar 

  25. Kasahara K, Kawakami Y, Kiyono T et al (2014) Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension. Nat Commun 5:5081

    Article  CAS  PubMed  Google Scholar 

  26. Xu J, Li H, Wang B et al (2010) VHL inactivation induces HEF1 and Aurora kinase a. J Am Soc Nephrol 21:2041–2046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shearer RF, Frikstad KM, McKenna J et al (2018) The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia. Mol Biol Cell 29:1542–1554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Das A, Qian J, Tsang WY (2017) USP9X counteracts differential ubiquitination of NPHP5 by MARCH7 and BBS11 to regulate ciliogenesis. PLoS Genet 13:e1006791

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Urbé S, Liu H, Hayes SD et al (2012) Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosome- and microtubule-associated functions. Mol Biol Cell 23:1095–1103

    Article  PubMed  PubMed Central  Google Scholar 

  30. Massa F, Tammaro R, Prado MA et al (2019) The deubiquitinating enzyme Usp14 controls ciliogenesis and hedgehog signaling. Hum Mol Genet 28:764–777

    Article  CAS  PubMed  Google Scholar 

  31. Eguether T, Ermolaeva MA, Zhao Y et al (2014) The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells. Nat Commun 5:4585

    Article  CAS  PubMed  Google Scholar 

  32. Kasahara K, Aoki H, Kiyono T et al (2018) EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase. Nat Commun 9:758

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Esquerdo-Barragán M, Brooks MJ, Toulis V, Swaroop A, Marfany G (2019) Expression of deubiquitinating enzyme genes in the developing mammal retina. Mol Vis 25:800–813

    Google Scholar 

  34. Cadavid AL, Ginzel A, Fischer JA (2000) The function of the Drosophila fat facets deubiquitinating enzyme in limiting photore-ceptor cell number is intimately associated with endocytosis. Development 127:1727–1736

    CAS  PubMed  Google Scholar 

  35. Ling X, Huang Q, Xu Y et al (2017) The deubiquitinating enzyme Usp5 regulates Notch and RTK signaling during Drosophila eye development. FEBS Lett 591:875–888

    Article  CAS  PubMed  Google Scholar 

  36. Thao DTP, An PNT, Yamaguchi M, LinhThuoc T (2012) Overexpression of ubiquitin carboxyl terminal hydrolase impairs multiple pathways during eye development in Drosophila melanogaster. Cell Tissue Res 348:453–463

    Article  CAS  PubMed  Google Scholar 

  37. Toulis V, Garanto A, Marfany G (2016) Combining zebrafish and mouse models to test the function of deubiquitinating enzyme (dubs) genes in development: role of USP45 in the retina. Methods Mol Biol 1449:85–101

    Article  CAS  PubMed  Google Scholar 

  38. Campello L, Esteve-Rudd J, Cuenca N, Martín-Nieto J (2013) The ubiquitin-proteasome system in retinal health and disease. Mol Neurobiol 47:790–810

    Article  CAS  PubMed  Google Scholar 

  39. Friedman JS, Ray JW, Waseem N et al (2009) Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. Am J Hum Genet 84:792–800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hugosson T, Friedman JS, Ponjavic V et al (2010) Phenotype associated with mutation in the recently identified autosomal dominant retinitis pigmentosa KLHL7 gene. Arch Ophthalmol 128:772–778

    Article  CAS  PubMed  Google Scholar 

  41. Wen Y, Locke KJ, Klein M et al (2011) Phenotypic characterization of 3 families with autosomal dominant retinitis pigmentosa due to mutations in KLHL7. Arch Ophthalmol 129:1475–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Angius A, Uva P, Buers I et al (2016) Bi-allelic mutations in KLHL7 cause a Crisponi/CISS1-like phenotype associated with early-onset retinitis pigmentosa. Am J Hum Genet 99:236–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chakarova CF, Khanna H, Shah AZ et al (2011) TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein. Hum Mol Genet 20:975–987

    Article  CAS  PubMed  Google Scholar 

  44. Chakarova CF, Papaioannou MG, Khanna H et al (2007) Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. Am J Hum Genet 81:1098–1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bowne SJ, Sullivan LS, Gire AI et al (2008) Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa. Mol Vis 14:922–927

    PubMed  PubMed Central  Google Scholar 

  46. Martínez-Gimeno M, Gamundi MJ, Hernan I et al (2003) Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 44:2171–2177

    Article  PubMed  Google Scholar 

  47. Yi Z, Ouyang J, Sun W et al (2019) Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. J Med Genet 56:325–331

    Article  CAS  PubMed  Google Scholar 

  48. Chiang AP, Beck JS, Yen HJ et al (2006) Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci U S A 103:6287–6292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Work by VT and GM was supported by grants SAF2013-49069-C2-1-R and SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER), 2017 SGR 738 (Generalitat de Catalunya), and La Marató TV3 (Project Marató 201417-30-31-32) to GM. VT is fellow of the MINECO (BES-2014-068639, Spain).

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Authors and Affiliations

  1. Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Barcelona, Spain

    Vasileios Toulis & Gemma Marfany

  2. CIBERER, ISCIII, Universitat de Barcelona, Barcelona, Spain

    Vasileios Toulis & Gemma Marfany

  3. Institut de Biomedicina (IBUB-IRSJD), Universitat de Barcelona, Barcelona, Spain

    Gemma Marfany

Authors
  1. Vasileios Toulis
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  2. Gemma Marfany
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Correspondence to Gemma Marfany .

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Editors and Affiliations

  1. CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain

    Rosa Barrio

  2. CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain

    James D. Sutherland

  3. Centre Pierre Potier, ITAV, Toulouse Cedex 1, France

    Manuel S. Rodriguez

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Toulis, V., Marfany, G. (2020). By the Tips of Your Cilia: Ciliogenesis in the Retina and the Ubiquitin-Proteasome System. In: Barrio, R., Sutherland, J., Rodriguez, M. (eds) Proteostasis and Disease . Advances in Experimental Medicine and Biology, vol 1233. Springer, Cham. https://doi.org/10.1007/978-3-030-38266-7_13

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