Bioinformatic analysis of ciliary transition zone proteins reveals insights into the evolution of ciliopathy networks

BMC Genomics

Helen R Dawe¹  Kimberley Fry¹  Karen S Renzaglia²  Amy R Barker¹ 

[1]Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter EX4 4QD, UK

[2]Department of Plant Biology, Southern Illinois University, Carbondale IL 62901, USA

关键词: Evolution;    NPHP;    MKS;    Permeability;    Compartmentalisation;    Transition zone;    Cilia;    Ciliopathy;    (3–10);   

Others  :  856994
DOI  :  10.1186/1471-2164-15-531

 received in 2014-02-13, accepted in 2014-06-18,  发布年份 2014

【 摘 要 】

Background

Cilia are critical for diverse functions, from motility to signal transduction, and ciliary dysfunction causes inherited diseases termed ciliopathies. Several ciliopathy proteins influence developmental signalling and aberrant signalling explains many ciliopathy phenotypes. Ciliary compartmentalisation is essential for function, and the transition zone (TZ), found at the proximal end of the cilium, has recently emerged as a key player in regulating this process. Ciliary compartmentalisation is linked to two protein complexes, the MKS and NPHP complexes, at the TZ that consist largely of ciliopathy proteins, leading to the hypothesis that ciliopathy proteins affect signalling by regulating ciliary content. However, there is no consensus on complex composition, formation, or the contribution of each component.

Results

Using bioinformatics, we examined the evolutionary patterns of TZ complex proteins across the extant eukaryotic supergroups, in both ciliated and non-ciliated organisms. We show that TZ complex proteins are restricted to the proteomes of ciliated organisms and identify a core conserved group (TMEM67, CC2D2A, B9D1, B9D2, AHI1 and a single TCTN, plus perhaps MKS1) which are present in >50% of all ciliate/flagellate organisms analysed in each supergroup. The smaller NPHP complex apparently evolved later than the larger MKS complex; this result may explain why RPGRIP1L, which forms the linker between the two complexes, is not one of the core conserved proteins. We also uncovered a striking correlation between lack of TZ proteins in non-seed land plants and loss of TZ-specific ciliary Y-links that link microtubule doublets to the membrane, consistent with the interpretation that these proteins are structural components of Y-links, or regulators of their formation.

Conclusions

This bioinformatic analysis represents the first systematic analysis of the cohort of TZ complex proteins across eukaryotic evolution. Given the near-ubiquity of only 6 proteins across ciliated eukaryotes, we propose that the MKS complex represents a dynamic complex built around these 6 proteins and implicated in Y-link formation and ciliary permeability.

【 授权许可】

   
2014 Barker et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Carvalho-Santos Z, Azimzadeh J, Pereira-Leal JB, Bettencourt-Dias M: Evolution: Tracing the origins of centrioles, cilia, and flagella. J Cell Biol 2011, 194(2):165-175.
• [2]Satir P, Mitchell DR, Jekely G: How did the cilium evolve? Curr Top Dev Biol 2008, 85:63-82.
• [3]Briggs LJ, Davidge JA, Wickstead B, Ginger ML, Gull K: More than one way to build a flagellum: comparative genomics of parasitic protozoa. Curr Biol 2004, 14(15):R611-R612.
• [4]Carvalho-Santos Z, Machado P, Branco P, Tavares-Cadete F, Rodrigues-Martins A, Pereira-Leal JB, Bettencourt-Dias M: Stepwise evolution of the centriole-assembly pathway. J Cell Sci 2010, 123(9):1414-1426.
• [5]Adams M, Smith UM, Logan CV, Johnson CA: Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. J Med Genet 2008, 45(5):257-267.
• [6]Waters AM, Beales PL: Ciliopathies: an expanding disease spectrum. Pediatr Nephrol 2011, 26(7):1039-1056.
• [7]Berbari NF, O'Connor AK, Haycraft CJ, Yoder BK: The primary cilium as a complex signaling center. Curr Biol 2009, 19(13):R526-R535.
• [8]Christensen ST, Pedersen LB, Schneider L, Satir P: Sensory cilia and integration of signal transduction in human health and disease. Traffic 2007, 8(2):97-109.
• [9]Goetz SC, Anderson KV: The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 2010, 11(5):331-344.
• [10]Wallingford JB, Mitchell B: Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia. Genes Dev 2011, 25(3):201-213.
• [11]Bloodgood RA: The future of ciliary and flagellar membrane research. Mol Biol Cell 2012, 23(13):2407-2411.
• [12]Hu Q, Milenkovic L, Jin H, Scott MP, Nachury MV, Spiliotis ET, Nelson WJ: A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science 2010, 329(5990):436-439.
• [13]Dishinger JF, Kee HL, Jenkins PM, Fan S, Hurd TW, Hammond JW, Truong YN, Margolis B, Martens JR, Verhey KJ: Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol 2010, 12(7):703-710.
• [14]Hurd TW, Fan S, Margolis BL: Localization of retinitis pigmentosa 2 to cilia is regulated by Importin beta2. J Cell Sci 2011, 124(Pt 5):718-726.
• [15]Kee HL, Dishinger JF, Blasius TL, Liu CJ, Margolis B, Verhey KJ: A size-exclusion permeability barrier and nucleoporins characterize a ciliary pore complex that regulates transport into cilia. Nat Cell Biol 2012, 14(4):431-437.
• [16]Francis SS, Sfakianos J, Lo B, Mellman I: A hierarchy of signals regulates entry of membrane proteins into the ciliary membrane domain in epithelial cells. J Cell Biol 2011, 193(1):219-233.
• [17]Chih B, Liu P, Chinn Y, Chalouni C, Komuves LG, Hass PE, Sandoval W, Peterson AS: A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol 2012, 14(1):61-72.
• [18]Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ, García-Verdugo JM, Katsanis N, Hildebrandt F, Reiter JF: A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 2011, 43(8):776-784.
• [19]Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, Baye LM, Wen X, Scales SJ, Kwong M, Huntzicker EG, Sfakianos MK, Sandoval W, Bazan JF, Kulkarni P, Garcia-Gonzalo FR, Seol AD, O'Toole JF, Held S, Reutter HM, Lane WS, Rafiq MA, Noor A, Ansar M, Devi AR, Sheffield VC, Slusarski DC, Vincent JB, Doherty DA, Hildebrandt F, et al.: Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 2011, 145(4):513-528.
• [20]Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE, Yoder BK, Leroux MR: MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 2011, 192(6):1023-1041.
• [21]Reiter JF, Blacque OE, Leroux MR: The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization. EMBO Rep 2012, 13(7):608-618.
• [22]Garcia-Gonzalo FR, Reiter JF: Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access. J Cell Biol 2012, 197(6):697-709.
• [23]Huang L, Szymanska K, Jensen VL, Janecke AR, Innes AM, Davis EE, Frosk P, Li C, Willer JR, Chodirker BN, Greenberg CR, McLeod DR, Bernier FP, Chudley AE, Müller T, Shboul M, Logan CV, Loucks CM, Beaulieu CL, Bowie RV, Bell SM, Adkins J, Zuniga FI, Ross KD, Wang J, Ban MR, Becker C, Nürnberg P, Douglas S, Craft CM, et al.: TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet 2011, 89(6):713-730.
• [24]Craige B, Tsao CC, Diener DR, Hou Y, Lechtreck KF, Rosenbaum JL, Witman GB: CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content. J Cell Biol 2010, 190(5):927-940.
• [25]Simpson AG, Roger AJ: The real 'kingdoms' of eukaryotes. Curr Biol 2004, 14(17):R693-R696.
• [26]Hodges ME, Scheumann N, Wickstead B, Langdale JA, Gull K: Reconstructing the evolutionary history of the centriole from protein components. J Cell Sci 2010, 123(Pt 9):1407-1413.
• [27]Tallila J, Jakkula E, Peltonen L, Salonen R, Kestilä M: Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy Puzzle. Am J Hum Genet 2008, 82(6):1361-1367.
• [28]Gorden NT, Arts HH, Parisi MA, Coene KLM, Letteboer SJF, Van Beersum SEC, Mans DA, Hikida A, Eckert M, Knutzen D, Alswaid AF, Ozyurek H, Dibooglu S, Otto EA, Liu Y, Davis EE, Hutter CM, Bammler TK, Farin FM, Dorschner M, Topçu M, Zackai EH, Rosenthal P, Owens KN, Katsanis N, Vincent JB, Hildebrandt F, Rubel EW, Raible DW, Knoers NV, et al.: CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290. Am J Hum Genet 2008, 83(5):559-571.
• [29]Hopp K, Heyer CM, Hommerding CJ, Henke SA, Sundsbak JL, Patel S, Patel P, Consugar MB, Czarnecki PG, Gliem TJ, Torres VE, Rossetti S, Harris PC: B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Hum Mol Genet 2011, 20(13):2524-2534.
• [30]Dowdle WE, Robinson JF, Kneist A, Sirerol-Piquer MS, Frints SGM, Corbit KC, Zaghloul NA, Van Lijnschoten G, Mulders L, Dideke VE, Zerres K, Reed RR, Attié-Bitach T, Johnson CA, García-Verdugo JM, Katsanis N, Bergmann C, Reiter JF: Disruption of a Ciliary B9 Protein Complex Causes Meckel Syndrome. Am J Hum Genet 2011, 89(1):94-110.
• [31]Shaheen R, Faqeih E, Seidahmed MZ, Sunker A, Alali FE, Khadijah A, Alkuraya FS: A TCTN2 mutation defines a novel Meckel Gruber syndrome locus. Hum Mutat 2011, 32(6):573-578.
• [32]Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA: Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 2004, 36(9):1008-1013.
• [33]Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, Morgan NV, Goranson E, Gissen P, Lilliquist S, Aligianis IA, Ward CJ, Pasha S, Punyashthiti R, Malik Sharif S, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Cox P, Algazali L, Trembath RC, Torres VE, Attie-Bitach T, Kelly DA, Maher ER, Gattone VH 2nd, Harris PC, et al.: The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 2006, 38(2):191-196.
• [34]Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, Ozilou C, Faivre L, Laurent N, Foliguet B, Munnich A, Lyonnet S, Salomon R, Encha-Razavi F, Gubler MC, Boddaert N, de Lonlay P, Johnson CA, Vekemans M, Antignac C, Attie-Bitach T: The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome. Am J Hum Genet 2007, 80(1):186-194.
• [35]Alazami AM, Alshammari MJ, Salih MA, Alzahrani F, Hijazi H, Seidahmed MZ, Abu Safieh L, Aldosary M, Khan AO, Alkuraya FS: Molecular characterization of Joubert syndrome in Saudi Arabia. Hum Mutat 2012, 33(10):1423-1428.
• [36]Dawson SC, House SA: Life with eight flagella: flagellar assembly and division in Giardia. Curr Opin Microbiol 2010, 13(4):480-490.
• [37]Van Dam TJP, Townsend MJ, Turk M, Schlessinger A, Sali A, Field MC, Huynen MA: Evolution of modular intraflagellar transport from a coatomer-like progenitor. Proc Natl Acad Sci U S A 2013, 110(17):6943-6948.
• [38]Sinden RE, Talman A, Marques SR, Wass MN, Sternberg MJE: The flagellum in malarial parasites. Curr Opin Microbiol 2010, 13(4):491-500.
• [39]Ferguson DJ, Hutchison WM, Dunachie JF, Siim JC: Ultrastructural study of early stages of asexual multiplication and microgametogony of Toxoplasma gondii in the small intestine of the cat. Acta Pathol Microbiol Scand B Microbiol Immunol 1974, 82(2):167-181.
• [40]De Leon JC, Scheumann N, Beatty W, Beck JR, Tran JQ, Yau C, Bradley PJ, Gull K, Wickstead B, Morrissette NS: A SAS-6-Like protein suggests that the toxoplasma conoid complex evolved from flagellar components. Eukaryot Cell 2013, 12(7):1009-1019.
• [41]Hodges ME, Wickstead B, Gull K, Langdale JA: The evolution of land plant cilia. New Phytol 2012, 195(3):526-540.
• [42]Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, Hildebrandt F, Otto EA, Held S, Diplas BH, Davis EE, Mikula M, Strom CM, Ben-Zeev B, et al.: Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 2010, 42(7):619-625.
• [43]Delous M, Hellman NE, Gaudé H-M, Silbermann F, Le Bivic A, Salomon R, Antignac C, Saunier S: Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6. Hum Mol Genet 2009, 18(24):4711-4723.
• [44]Simms R, Hynes A, Eley L, Inglis D, Chaudhry B, Dawe H, Sayer J: Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development. Cell Mol Life Sci 2012, 69(6):993-1009.
• [45]Veland IR, Montjean R, Eley L, Pedersen LB, Schwab A, Goodship J, Kristiansen K, Pedersen SF, Saunier S, Christensen ST: Inversin/Nephrocystin-2 Is Required for Fibroblast Polarity and Directional Cell Migration. PLoS One 2013, 8(4):e60193.
• [46]Choi HJ, Lin JR, Vannier JB, Slaats GG, Kile AC, Paulsen RD, Manning DK, Beier DR, Giles RH, Boulton SJ, Cimprich KA: NEK8 Links the ATR-Regulated Replication Stress Response and S Phase CDK Activity to Renal Ciliopathies. Mol Cell 2013, 51(4):423-439.
• [47]Borgal L, Habbig S, Hatzold J, Liebau MC, Dafinger C, Sacarea I, Hammerschmidt M, Benzing T, Schermer B: The Ciliary Protein Nephrocystin-4 Translocates the Canonical Wnt Regulator Jade-1 to the Nucleus to Negatively Regulate β-Catenin Signaling. J Biol Chem 2012, 287(30):25370-25380.
• [48]Werner ME, Ward HH, Phillips CL, Miller C, Gattone VH, Bacallao RL: Inversin modulates the cortical actin network during mitosis. Am J Physiol Cell Physiol 2013, 305(1):C36-C47.
• [49]Wheway G, Abdelhamed Z, Natarajan S, Toomes C, Inglehearn C, Johnson CA: Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel–Gruber syndrome. Dev Biol 2013, 377(1):55-66.
• [50]Abdelhamed ZA, Wheway G, Szymanska K, Natarajan S, Toomes C, Inglehearn C, Johnson CA: Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel–Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum Mol Genet 2013, 22(7):1358-1372.
• [51]Leightner AC, Hommerding CJ, Peng Y, Salisbury JL, Gainullin VG, Czarnecki PG, Sussman CR, Harris PC: The Meckel syndrome protein meckelin (TMEM67) is a key regulator of cilia function but is not required for tissue planar polarity. Hum Mol Genet 2013, 22(10):2024-2040.
• [52]Dawe HR, Adams M, Wheway G, Szymanska K, Logan CV, Noegel AA, Gull K, Johnson CA: Nesprin-2 interacts with meckelin and mediates ciliogenesis via remodelling of the actin cytoskeleton. J Cell Sci 2009, 122(15):2716-2726.
• [53]Richards GS, Degnan BM: The dawn of developmental signaling in the metazoa. Cold Spring Harb Symp Quant Biol 2009, 74:81-90.
• [54]Dickinson DJ, Nelson WJ, Weis WI: A Polarized Epithelium Organized by β- and α-Catenin Predates Cadherin and Metazoan Origins. Science 2011, 331(6022):1336-1339.
• [55]Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, et al.: The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006, 38(6):674-681.
• [56]Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL, Blair-Reid S, Sriram N, Katsanis N, Attie-Bitach T, Afford SC, Copp AJ, Kelly DA, Gull K, Johnson CA: The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet 2007, 16(2):173-186.
• [57]Keller LC, Romijn EP, Zamora I, Yates Iii JR, Marshall WF: Proteomic analysis of isolated chlamydomonas centrioles reveals orthologs of ciliary-disease genes. Curr Biol 2005, 15(12):1090-1098.
• [58]Hsiao Y-C, Tong ZJ, Westfall JE, Ault JG, Page-McCaw PS, Ferland RJ: Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis, and vesicle trafficking. Hum Mol Genet 2009, 18(20):3926-3941.
• [59]Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 1997, 25(17):3389-3402.
• [60]Camacho C, Coulouris G, Avagyan V, Ma N, Papadopoulos J, Bealer K, Madden TL: BLAST+: architecture and applications. BMC Bioinformatics 2009, 10:421.
• [61]Katoh K, Misawa K, Kuma K, Miyata T: MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res 2002, 30(14):3059-3066.
• [62]Katoh K, Toh H: Recent developments in the MAFFT multiple sequence alignment program. Brief Bioinform 2008, 9:286-298.
• [63]Eddy SR: Accelerated Profile HMM Searches. PLoS Comput Biol 2011, 7(10):e1002195.
• [64]Goujon M, McWilliam H, Li W, Valentin F, Squizzato S, Paern J, Lopez R: A new bioinformatics analysis tools framework at EMBL–EBI. Nucleic Acids Res 2010, 38(suppl 2):W695-W699.
• [65]Zdobnov EM, Apweiler R: InterProScan – an integration platform for the signature-recognition methods in InterPro. Bioinformatics 2001, 17(9):847-848.