A NIMA-Related Kinase Suppresses the Flagellar Instability Associated with the Loss of Multiple Axonemal Structures

English version České info

Cilia are specialized projections found on the surface of eukaryotic cells. They play crucial sensory functions, as well as motile functions needed for clearing airways or propelling cells. Ciliary motility is perturbed in the inherited disease, Primary Ciliary Dyskinesia (PCD). Two coiled coil domain-containing (CCDC39 and CCDC40) proteins are needed for the assembly of multiple key structures/complexes that are required for generating ciliary motility. Using the unicellular green alga, Chlamydomonas, we have identified a kinase (CNK11) that when mutated is able to partially rescue the short flagella phenotype of the ccdc39 and ccdc40 mutants as well as mutants lacking axonemal dyneins or the N-DRC complex. In addition, CCDC40 is required for tubulin polyglutamylation at the proximal end of flagella. We suggest that substructures like dynein arms and the N-DRC, which are needed for motility, play a second role in stabilizing the axonemal microtubules and are needed for proper length control. The polyglutamylase, TTLL9, and the kinase, CNK11, play roles in stabilizing the axonemal microtubules based on their ability to partially rescue the short flagella phenotypes of multiple mutants.

Vyšlo v časopise: A NIMA-Related Kinase Suppresses the Flagellar Instability Associated with the Loss of Multiple Axonemal Structures. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005508
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005508

Souhrn

Zdroje

1. Zariwala MA, Omran H, Ferkol TW: The emerging genetics of primary ciliary dyskinesia. Proceedings of the American Thoracic Society 2011, 8:430–433.

2. Olbrich H, Haffner K, Kispert A, Volkel A, Volz A, Sasmaz G, Reinhardt R, Hennig S, Lehrach H, Konietzko N, et al: Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nature genetics 2002, 30:143–144.

3. Zariwala MA, Leigh MW, Ceppa F, Kennedy MP, Noone PG, Carson JL, Hazucha MJ, Lori A, Horvath J, Olbrich H, et al: Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. American journal of respiratory and critical care medicine 2006, 174:858–866.

4. Mitchison HM, Schmidts M, Loges NT, Freshour J, Dritsoula A, Hirst RA, O'Callaghan C, Blau H, Al Dabbagh M, Olbrich H, et al: Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia. Nature genetics 2012, 44:381–389, S381–382.

5. Diggle CP, Moore DJ, Mali G, Zur Lage P, Ait-Lounis A, Schmidts M, Shoemark A, Garcia Munoz A, Halachev MR, Gautier P, et al: HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus. PLoS genetics 2014, 10:e1004577.

6. Horani A, Druley TE, Zariwala MA, Patel AC, Levinson BT, Van Arendonk LG, Thornton KC, Giacalone JC, Albee AJ, Wilson KS, et al: Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia. American journal of human genetics 2012, 91:685–693.

7. Gao C, Wang G, Amack JD, Mitchell DR: Oda16/Wdr69 is essential for axonemal dynein assembly and ciliary motility during zebrafish embryogenesis. Developmental dynamics: an official publication of the American Association of Anatomists 2010, 239:2190–2197.

8. Ahmed NT, Gao C, Lucker BF, Cole DG, Mitchell DR: ODA16 aids axonemal outer row dynein assembly through an interaction with the intraflagellar transport machinery. J Cell Biol 2008, 183:313–322.

9. Wirschell M, Olbrich H, Werner C, Tritschler D, Bower R, Sale WS, Loges NT, Pennekamp P, Lindberg S, Stenram U, et al: The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nature genetics 2013, 45:262–268.

10. Bower R, Tritschler D, Vanderwaal K, Perrone CA, Mueller J, Fox L, Sale WS, Porter ME: The N-DRC forms a conserved biochemical complex that maintains outer doublet alignment and limits microtubule sliding in motile axonemes. Molecular biology of the cell 2013, 24:1134–1152.

11. Antony D, Becker-Heck A, Zariwala MA, Schmidts M, Onoufriadis A, Forouhan M, Wilson R, Taylor-Cox T, Dewar A, Jackson C, et al: Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Human mutation 2013, 34:462–472.

12. Blanchon S, Legendre M, Copin B, Duquesnoy P, Montantin G, Kott E, Dastot F, Jeanson L, Cachanado M, Rousseau A, et al: Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. Journal of medical genetics 2012, 49:410–416.

13. Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, Yagi H, Khalifa O, Kureshi S, Chatterjee B, et al: High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation 2012, 125:2232–2242.

14. Merveille AC, Davis EE, Becker-Heck A, Legendre M, Amirav I, Bataille G, Belmont J, Beydon N, Billen F, Clement A, et al: CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nature genetics 2011, 43:72–78.

15. Becker-Heck A, Zohn IE, Okabe N, Pollock A, Lenhart KB, Sullivan-Brown J, McSheene J, Loges NT, Olbrich H, Haeffner K, et al: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nature genetics 2011, 43:79–84.

16. Oda T, Yanagisawa H, Kamiya R, Kikkawa M: Cilia and flagella. A molecular ruler determines the repeat length in eukaryotic cilia and flagella. Science 2014, 346:857–860.

17. McVittie A: Flagellum mutants of Chlamydomonas reinhardii. J Gen Microbiol 1972, 71:525–540.

18. Davis SD, Ferkol TW, Rosenfeld M, Lee H-S, Dell SD, Sagel SD, Milla C, Zariwala MA, Pittman JE, Shapiro AJ, et al: Clinical Features of Childhood Primary Ciliary Dyskinesia by Genotype and Ultrastructural Phenotype. American journal of respiratory and critical care medicine 2015, 191:316–324.

19. Marshall WF, Qin H, Rodrigo Brenni M, Rosenbaum JL: Flagellar length control system: testing a simple model based on intraflagellar transport and turnover. Molecular biology of the cell 2005, 16:270–278.

20. Lin H, Nauman NP, Albee AJ, Hsu S, Dutcher SK: New mutations in flagellar motors identified from whole genome sequencing in Chlamydomonas reinhardtii. Cilia 2013, 2:14.

21. Iomini C, Li L, Esparza JM, Dutcher SK: Retrograde intraflagellar transport mutants identify complex A proteins with multiple genetic interactions in Chlamydomonas reinhardtii. Genetics 2009, 183:885–896.

22. Wang L, Piao T, Cao M, Qin T, Huang L, Deng H, Mao T, Pan J: Flagellar regeneration requires cytoplasmic microtubule depolymerization and kinesin-13. Journal of cell science 2013, 126:1531–1540.

23. Kannegaard E, Rego EH, Schuck S, Feldman JL, Marshall WF: Quantitative analysis and modeling of katanin function in flagellar length control. Molecular biology of the cell 2014, 25:3686–3698.

24. King SJ, Dutcher SK: Phosphoregulation of an inner dynein arm complex in Chlamydomonas reinhardtii is altered in phototactic mutant strains. J Cell Biol 1997, 136:177–191.

25. Piperno G, Ramanis Z, Smith EF, Sale WS: Three distinct inner dynein arms in Chlamydomonas flagella: molecular composition and location in the axoneme. J Cell Biol 1990, 110:379–389.

26. LeDizet M, Piperno G: The light chain p28 associates with a subset of inner dynein arm heavy chains in Chlamydomonas axonemes. Molecular biology of the cell 1995, 6:697–711.

27. Kubo T, Hirono M, Aikawa T, Kamiya R, Witman GB: Reduced tubulin polyglutamylation suppresses flagellar shortness in Chlamydomonas. Molecular biology of the cell 2015, 26:2810–2822.

28. Kubo T, Yanagisawa HA, Liu Z, Shibuya R, Hirono M, Kamiya R: A conserved flagella-associated protein in Chlamydomonas, FAP234, is essential for axonemal localization of tubulin polyglutamylase TTLL9. Molecular biology of the cell 2014, 25:107–117.

29. Kubo T, Yanagisawa H-a, Yagi T, Hirono M, Kamiya R: Tubulin Polyglutamylation Regulates Axonemal Motility by Modulating Activities of Inner-Arm Dyneins. Current Biology 2010, 20:441–445.

30. Song Y, Brady ST: Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends in Cell Biology 2015, 25:125–136.

31. Janke C, Chloë Bulinski J: Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions. Nat Rev Mol Cell Biol 2011, 12:773–786.

32. Wloga D, Gaertig J: Post-translational modifications of microtubules. Journal of cell science 2010, 123:3447–3455.

33. Parker JD, Bradley BA, Mooers AO, Quarmby LM: Phylogenetic analysis of the Neks reveals early diversification of ciliary-cell cycle kinases. PLoS One 2007, 2:e1076.

34. O'Regan L, Blot J, Fry A: Mitotic regulation by NIMA-related kinases. Cell Division 2007, 2:25.

35. Mahjoub MR, Qasim Rasi M, Quarmby LM: A NIMA-related kinase, Fa2p, localizes to a novel site in the proximal cilia of Chlamydomonas and mouse kidney cells. Molecular biology of the cell 2004, 15:5172–5186.

36. Hilton LK, Gunawardane K, Kim JW, Schwarz MC, Quarmby LM: The kinases LF4 and CNK2 control ciliary length by feedback regulation of assembly and disassembly rates. Curr Biol 2013, 23:1–7.

37. Doles J, Hemann MT: Nek4 status differentially alters sensitivity to distinct microtubule poisons. Cancer research 2010, 70:1033–1041.

38. Motose H, Takatani S, Ikeda T, Takahashi T: NIMA-related kinases regulate directional cell growth and organ development through microtubule function in Arabidopsis thaliana. Plant Signaling & Behavior 2012, 7:1552–1555.

39. McVittie A: Studies on flagella-less, stumpy, and short flagellum mutants of Chlamydomonas reinhardii. Proceedings of the Royal Society of London Series B, Containing papers of a Biological character Royal Society 1969, 173:59–60.

40. Ramanis Z, Luck DJ: Loci affecting flagellar assembly and function map to an unusual linkage group in Chlamydomonas reinhardtii. Proc Natl Acad Sci U S A 1986, 83:423–426.

41. Dutcher SK: Genetic properties of linkage group XIX in Chlamydomonas reinhardtii. Basic Life Sci 1986, 40:303–325.

42. Lin H, Miller ML, Granas DM, Dutcher SK: Whole Genome Sequencing Identifies a Deletion in Protein Phosphatase 2A That Affects Its Stability and Localization in Chlamydomonas reinhardtii. PLoS genetics 2013, 9:e1003841.

43. Adams GM, Huang B, Luck DJ: Temperature-sensitive, assembly-defective flagella mutants of Chlamydomonas reinhardtii. Genetics 1982, 100:579–586.

44. Huang B, Ramanis Z, Luck DJ: Suppressor mutations in Chlamydomonas reveal a regulatory mechanism for Flagellar function. Cell 1982, 28:115–124.

45. Porter ME, Power J, Dutcher SK: Extragenic suppressors of paralyzed flagellar mutations in Chlamydomonas reinhardtii identify loci that alter the inner dynein arms. J Cell Biol 1992, 118:1163–1176.

46. Yanagisawa HA, Kamiya R: A tektin homologue is decreased in chlamydomonas mutants lacking an axonemal inner-arm dynein. Molecular biology of the cell 2004, 15:2105–2115.

47. Yagi T, Uematsu K, Liu Z, Kamiya R: Identification of dyneins that localize exclusively to the proximal portion of Chlamydomonas flagella. Journal of cell science 2009, 122:1306–1314.

48. Yang P, Sale WS: The Mr 140,000 intermediate chain of Chlamydomonas flagellar inner arm dynein is a WD-repeat protein implicated in dynein arm anchoring. Molecular biology of the cell 1998, 9:3335–3349.

49. Perrone CA, Yang P, O'Toole E, Sale WS, Porter ME: The Chlamydomonas IDA7 locus encodes a 140-kDa dynein intermediate chain required to assemble the I1 inner arm complex. Molecular biology of the cell 1998, 9:3351–3365.

50. King SM, Kamiya R: Axonemal Dyneins: Assembly, strucure and force generation. In The Chlamydomonas Sourcebook, Second Edition Volume 3: Cell Motility and Behavior. Edited by Witman GB. Amsterdam: Elsevier; 2009: 131–208

51. Salisbury JL, Baron AT, Sanders MA: The centrin-based cytoskeleton of Chlamydomonas reinhardtii: distribution in interphase and mitotic cells. J Cell Biol 1988, 107:635–641.

52. Yang C, Compton MM, Yang P: Dimeric novel HSP40 is incorporated into the radial spoke complex during the assembly process in flagella. Molecular biology of the cell 2005, 16:637–648.

53. Mitchell DR, Kang Y: Identification of oda6 as a Chlamydomonas dynein mutant by rescue with the wild-type gene. J Cell Biol 1991, 113:835–842.

54. King SM, Otter T, Witman GB: Characterization of monoclonal antibodies against Chlamydomonas flagellar dyneins by high-resolution protein blotting. Proceedings of the National Academy of Sciences 1985, 82:4717–4721.

55. Linck RW, Norrander JM: Protofilament ribbon compartments of ciliary and flagellar microtubules. Protist 2003, 154:299–311.

56. Norrander JM, deCathelineau AM, Brown JA, Porter ME, Linck RW: The Rib43a protein is associated with forming the specialized protofilament ribbons of flagellar microtubules in Chlamydomonas. Molecular biology of the cell 2000, 11:201–215.

57. Tam LW, Ranum PT, Lefebvre PA: CDKL5 regulates flagellar length and localizes to the base of the flagella in Chlamydomonas. Molecular biology of the cell 2013, 24:588–600.

58. Iomini C, Babaev-Khaimov V, Sassaroli M, Piperno G: Protein particles in Chlamydomonas flagella undergo a transport cycle consisting of four phases. J Cell Biol 2001, 153:13–24.

59. Wren KN, Craft JM, Tritschler D, Schauer A, Patel DK, Smith EF, Porter ME, Kner P, Lechtreck KF: A differential cargo-loading model of ciliary length regulation by IFT. Curr Biol 2013, 23:2463–2471.

60. Dymek EE, Lefebvre PA, Smith EF: PF15p is the chlamydomonas homologue of the Katanin p80 subunit and is required for assembly of flagellar central microtubules. Eukaryot Cell 2004, 3:870–879.

61. Wirschell M, Olbrich H, Werner C, Tritschler D, Bower R, Sale WS, Loges NT, Pennekamp P, Lindberg S, Stenram U, et al: The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nature genetics 2013, 45:262–268.

62. Huang B, Piperno G, Luck DJ: Paralyzed flagella mutants of Chlamydomonas reinhardtii. Defective for axonemal doublet microtubule arms. Journal of Biological Chemistry 1979, 254:3091–3099.

63. Kamiya R: Exploring the function of inner and outer dynein arms with Chlamydomonas mutants. Cell Motility and the Cytoskeleton 1995, 32:98–102.

64. Esparza JM, O'Toole E, Li L, Giddings TH Jr., Kozak B, Albee AJ, Dutcher SK: Katanin localization requires triplet microtubules in Chlamydomonas reinhardtii. PLoS One 2013, 8:e53940.

65. Audebert S, Desbruyères E, Gruszczynski C, Koulakoff A, Gros F, Denoulet P, Eddé B: Reversible polyglutamylation of alpha- and beta-tubulin and microtubule dynamics in mouse brain neurons. Molecular biology of the cell 1993, 4:615–626.

66. Avasthi P, Marshall WF: Stages of ciliogenesis and regulation of ciliary length. Differentiation 2012, 83:S30–S42.

67. Silflow CD, Lefebvre PA: Assembly and Motility of Eukaryotic Cilia and Flagella. Lessons from Chlamydomonas reinhardtii. Plant Physiology 2001, 127:1500–1507.

68. Wilson NF, Iyer JK, Buchheim JA, Meek W: Regulation of flagellar length in Chlamydomonas. Seminars in Cell & Developmental Biology 2008, 19:494–501.

69. Cao M, Li G, Pan J: Chapter 17—Regulation of Cilia assembly, Disassembly, and Length by Protein Phosphorylation. In Methods in Cell Biology. Volume Volume 94. Edited by Roger DS: Academic Press; 2009: 333–346

70. Randall J, STARLING D: Chapter 3—Genetic determinants of flagellum phenotype in Chlamydomonas reinhardii. In The Genetics of Algae. Volume 12. Edited by Lewin RA: University of California Press; 1976: 49–62

71. Bui KH, Yagi T, Yamamoto R, Kamiya R, Ishikawa T: Polarity and asymmetry in the arrangement of dynein and related structures in the Chlamydomonas axoneme. The Journal of Cell Biology 2012, 198:913–925.

72. Kubo T, Yagi T, Kamiya R: Tubulin polyglutamylation regulates flagellar motility by controlling a specific inner-arm dynein that interacts with the dynein regulatory complex. Cytoskeleton 2012, 69:1059–1068.

73. Suryavanshi S, Eddé B, Fox LA, Guerrero S, Hard R, Hennessey T, Kabi A, Malison D, Pennock D, Sale WS, et al: Tubulin Glutamylation Regulates Ciliary Motility by Altering Inner Dynein Arm Activity. Current Biology 2010, 20:435–440.

74. Ikegami K, Sato S, Nakamura K, Ostrowski LE, Setou M: Tubulin polyglutamylation is essential for airway ciliary function through the regulation of beating asymmetry. Proceedings of the National Academy of Sciences 2010, 107:10490–10495.

75. Wloga D, Dave D, Meagley J, Rogowski K, Jerka-Dziadosz M, Gaertig J: Hyperglutamylation of tubulin can either stabilize or destabilize microtubules in the same cell. Eukaryot Cell 2010, 9:184–193.

76. Yu I, Garnham CP, Roll-Mecak A: Writing and Reading the Tubulin Code. Journal of Biological Chemistry 2015, 290:17163–17172.

77. Lacroix B, van Dijk J, Gold ND, Guizetti J, Aldrian-Herrada G, Rogowski K, Gerlich DW, Janke C: Tubulin polyglutamylation stimulates spastin-mediated microtubule severing. The Journal of Cell Biology 2010, 189:945–954.

78. LeDizet M, Piperno G: Cytoplasmic microtubules containing acetylated alpha-tubulin in Chlamydomonas reinhardtii: spatial arrangement and properties. The Journal of Cell Biology 1986, 103:13–22.

79. Pazour GJ, Agrin N, Leszyk J, Witman GB: Proteomic analysis of a eukaryotic cilium. The Journal of Cell Biology 2005, 170:103–113.

80. Wang H, Gau B, Slade WO, Juergens M, Li P, Hicks LM: The Global Phosphoproteome of Chlamydomonas reinhardtii Reveals Complex Organellar Phosphorylation in the Flagella and Thylakoid Membrane. Molecular & Cellular Proteomics 2014, 13:2337–2353.

81. Hu Z, Liang Y, He W, Pan J: Cilia Disassembly with Two Distinct Phases of Regulation. Cell Reports 2015, 10:1803–1810.

82. Tam L- W, Wilson NF, Lefebvre PA: A CDK-related kinase regulates the length and assembly of flagella in Chlamydomonas. The Journal of Cell Biology 2007, 176:819–829.

83. Berman SA, Wilson NF, Haas NA, Lefebvre PA: A Novel MAP Kinase Regulates Flagellar Length in Chlamydomonas. Current Biology 2003, 13:1145–1149.

84. Kuchka MR, Jarvik JW: Short-Flagella Mutants of Chlamydomonas reinhardtii. Genetics 1987, 115:685–691.

85. McVittie A: Genetic studies on flagellum mutants of Chlamydomonas reinhardii. Genetics Research 1972, 19:157–164.

86. Dutcher SK, Li L, Lin H, Meyer L, Giddings TH Jr., Kwan AL, Lewis BL: Whole-Genome Sequencing to Identify Mutants and Polymorphisms in Chlamydomonas reinhardtii. G3 2012, 2:15–22.

87. Palombella AL, Dutcher SK: Identification of the gene encoding the tryptophan synthase beta-subunit from Chlamydomonas reinhardtii. Plant Physiol 1998, 117:455–464.

88. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome Project Data Processing S: The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009, 25:2078–2079.

89. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, Land SJ, Lu X, Ruden DM: A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 2012, 6:80–92.

90. DeSantis MC, DeCenzo SH, Li JL, Wang YM: Precision analysis for standard deviation measurements of immobile single fluorescent molecule images. Optics express 2010, 18:6563–6576.