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Cited by 397Genetic and Kidney Cyst DiseasesCystic Fibrosis Research AdvancesHedgehog Signaling Pathway Studies

Establishing and regulating the composition of cilia for signal transduction

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Nachury, Maxence V., Mick, David U.·2019·Nature Reviews Molecular Cell Biology
DOI 10.1038/s41580-019-0116-4PMC PMC6738346
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Abstract

The primary cilium is a hair-like surface-exposed organelle of the eukaryotic cell that decodes a variety of signals - such as odorants, light and Hedgehog morphogens - by altering the local concentrations and activities of signalling proteins. Signalling within the cilium is conveyed through a diverse array of second messengers, including conventional signalling molecules (such as cAMP) and some unusual intermediates (such as sterols). Diffusion barriers at the ciliary base establish the unique composition of this signalling compartment, and cilia adapt their proteome to signalling demands through regulated protein trafficking. Much progress has been made on the molecular understanding of regulated ciliary trafficking, which encompasses not only exchanges between the cilium and the rest of the cell but also the shedding of signalling factors into extracellular vesicles.

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  • The primary cilium is involved in Ca2+, Hedgehog, PDGFRα, Notch, TGF-β, mTOR, and other signalling pathways, which regulate cell proliferation, maturation, and differentiation.

    “Moreover, the primary cilium is involved in Ca2+, Hedgehog (Hh), PDGFR⍺, Notch, TGF-β, mTOR, and other signalling pathways, which regulate cell proliferation, maturation, and differentiation (Pala et al. 2017; Nachury and Mick 2019; Mill et al. 2023).”

    From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Nachury and Mick 2019

    The Introduction (page unavailable) associates primary cilia with Hedgehog, Notch, PDGFRα and TGF-β signalling, and discusses ciliary regulation of Ca2+. It does not identify mTOR as a ciliary signalling pathway or establish that the listed pathways collectively regulate proliferation, maturation and differentiation. It also cautions that the physiological requirement for cilia in some associated pathways remains unresolved. (LLM, conf=0.88)

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  1. [2]de Robertis E Electron microscope observations on the submicroscopic organization of the retinal rods. The Journal of biophysical and biochemical cytology 2, 319– 330 (1956). PMC2223973 13331964
  2. [3]Bloom G Studies on the olfactory epithelium of the frog and the toad with the aid of light and electron microscopy. Zeitschrift für Zellforschung und Mikroskopische Anatomie 41, 89– 100 (1954). 14360477
  3. [4]Huangfu D Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83– 7 (2003). 14603322
  4. [5]Gerdes JM Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nature Genetics 39, 1350– 1360 (2007). 17906624
  5. [6]Ezratty EJ A Role for the Primary Cilium in Notch Signaling and Epidermal Differentiation during Skin Development. Cell 145, 1129– 1141 (2011). 21703454 PMC3135909
  6. [7]Ross AJ Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nature Genetics 37, 1135– 1140 (2005). 16170314
  7. [8]Schneider L PDGFRαα signaling is regulated through the primary cilium in fibroblasts. Current biology: CB 15, 1861– 1866 (2005). 16243034
  8. [9]Yeh C IGF-1 activates a cilium-localized noncanonical Gβγ signaling pathway that regulates cell-cycle progression. Developmental Cell 26, 358– 368 (2013). 23954591 PMC3790638
  9. [11]Clement CA TGF-β signaling is associated with endocytosis at the pocket region of the primary cilium. Cell reports 3, 1806– 1814 (2013). 23746451
  10. [13]Bloodgood RA Sensory reception is an attribute of both primary cilia and motile cilia. Journal of Cell Science 123, 505– 509 (2010). 20144998
  11. [14]Wachten D, Jikeli JF & Kaupp UB Sperm Sensory Signaling. Cold Spring Harbor Perspectives in Biology 9, a028225 (2017). 28062561 PMC5495058
  12. [15]Calvert PD, Schiesser WE & Pugh EN Diffusion of a soluble protein, photoactivatable GFP, through a sensory cilium. J. Gen. Physiol 135, 173– 196 (2010). 20176852 PMC2828910
  13. [16]Bhandawat V, Reisert J & Yau K-W Signaling by olfactory receptor neurons near threshold. PNAS 107, 18682– 18687 (2010). 20930117 PMC2972989
  14. [17]Corbit KC Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018– 1021 (2005). 16136078
  15. [18]Haycraft CJ Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1, e53 (2005). 16254602 PMC1270009
  16. [19]May SR Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Developmental Biology 287, 378– 389 (2005). 16229832
  17. [20]Belzile O, Hernandez-Lara CI, Wang Q & Snell WJ Regulated Membrane Protein Entry into Flagella Is Facilitated by Cytoplasmic Microtubules and Does Not Require IFT. Current Biology 23, 1460– 1465 (2013). 23891117 PMC3740039
  18. [21]Rohatgi R, Milenkovic L & Scott MP Patched1 regulates hedgehog signaling at the primary cilium. Science (New York, NY) 317, 372– 376 (2007). 17641202
  19. [22]Bangs F & Anderson KV Primary cilia and mammalian Hedgehog signaling. Cold Spring Harbor perspectives in biology 9, a028175 (2017). 27881449 PMC5411695
  20. [23]Pablo JL, DeCaen PG & Clapham DE Progress in ciliary ion channel physiology. The Journal of General Physiology 149, 37– 47 (2017). 27999145 PMC5217089
  21. [24]Johnson J-LF & Leroux MR cAMP and cGMP signaling: sensory systems with prokaryotic roots adopted by eukaryotic cilia. Trends in cell biology 20, 435– 444 (2010). 20541938
  22. [25]Garcia G, Raleigh DR & Reiter JF How the Ciliary Membrane Is Organized Inside-Out to Communicate Outside-In. Current Biology 28, R421– R434 (2018). 29689227 PMC6434934
  23. [26]Luchetti G Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling. eLife 5, e20304 (2016). 27705744 PMC5123864
  24. [27]Huang P Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling. Cell 166, 1176– 1187.e14 (2016). 27545348 PMC5035717
  25. [28]Raleigh DR Cilia-Associated Oxysterols Activate Smoothened. Molecular Cell 72, 316– 327.e5 (2018). 30340023 PMC6503851 This paper identifies the oxysterols 24,25-epoxycholesterol and 7β,27-dihydroxycholesterol as ciliary lipids that bind and activate Smoothened.
  26. [29]Nager AR An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling. Cell 168, 252– 263.e14 (2017). 28017328 PMC5235987 This paper uncovers signal-dependent ectocytosis as a means for ciliary exit of activated GPCRs in mammalian cells, see also 193. It also discovered a role for actin in ectosome scission, see also 30.
  27. [30]Phua SC Dynamic Remodeling of Membrane Composition Drives Cell Cycle through Primary Cilia Excision. Cell 168, 264– 279.e15 (2017). 28086093 PMC5660509 Discovery of a role for actin in ectosome release, see also 29. This study also suggests that cilia shorten by shedding ectosomes; see also 31.
  28. [31]Long H Comparative Analysis of Ciliary Membranes and Ectosomes. Curr. Biol 26, 3327– 3335 (2016). 27866888 PMC5173405 This study demonstrates that cilia shorten, at least in part, by shedding ectosomes, see also 30. It also suggests a role for ESCRT proteins ALG-2 and VPS-4 in ciliary ectocytosis.
  29. [32]Fisch C & Dupuis-Williams P Ultrastructure of cilia and flagella - back to the future! Biol Cell 103, 249– 70 (2011). 21728999
  30. [33]Garcia-Gonzalo FR & Reiter JF Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition. Cold Spring Harb Perspect Biol 9, a028134 (2017). 27770015 PMC5287074
  31. [34]Gonçalves J & Pelletier L The Ciliary Transition Zone: Finding the Pieces and Assembling the Gate. Mol. Cells 40, 243– 253 (2017). 28401750 PMC5424270
  32. [35]Breslow D, Koslover EF, Seydel F, Spakowitz AJ & Nachury MV An in vitro assay for entry into cilia reveals unique properties of the soluble diffusion barrier. The Journal of Cell Biology 203, 129– 147 (2013). 24100294 PMC3798247
  33. [36]Cevik S Active Transport and Diffusion Barriers Restrict Joubert Syndrome-Associated ARL13B/ARL-13 to an Inv-like Ciliary Membrane Subdomain. PLoS Genetics 9, e1003977 (2013). 24339792 PMC3854969
  34. [37]Chih B A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol 14, 61– 72 (2011). 22179047
  35. [38]Hu Q A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science (New York, NY) 329, 436– 439 (2010). PMC3092790 20558667
  36. [39]Kee HL A size-exclusion permeability barrier and nucleoporins characterize a ciliary pore complex that regulates transport into cilia. Nat Cell Biol 14, 431– 7 (2012). 22388888 PMC3319646
  37. [40]Lin Y-C Chemically inducible diffusion trap at cilia reveals molecular sieve-like barrier. Nat. Chem. Biol 9, 437– 443 (2013). 23666116 PMC3870470
  38. [41]Yang TT Super-resolution architecture of mammalian centriole distal appendages reveals distinct blade and matrix functional components. Nat Commun 9, 2023 (2018). 29789620 PMC5964178 Establishes the existence of the distal appendage matrix (DAM) and suggests that the DAM functions as a barrier for ciliary membrane proteins.
  39. [43]Najafi M, Maza NA & Calvert PD Steric volume exclusion sets soluble protein concentrations in photoreceptor sensory cilia. Proc Natl Acad Sci U S A 109, 203– 208 (2012). 22184246 PMC3252922
  40. [44]Lambacher NJ TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. Nat. Cell Biol 18, 122– 131 (2016). 26595381 PMC5580800
  41. [45]Takao D, Wang L, Boss A & Verhey KJ Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone. Current biology: CB 27, 2296– 2306.e3 (2017). 28736169 PMC5576555
  42. [46]Craige B CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content. J Cell Biol 190, 927– 40 (2010). 20819941 PMC2935561
  43. [47]Awata J NPHP4 controls ciliary trafficking of membrane proteins and large soluble proteins at the transition zone. Journal of Cell Science 127, 4714– 4727 (2014). 25150219 PMC4215714
  44. [48]Scheidel N & Blacque OE Intraflagellar Transport Complex A Genes Differentially Regulate Cilium Formation and Transition Zone Gating. Curr. Biol 28, 3279– 3287.e2 (2018). 30293716
  45. [49]Vuolo L, Stevenson NL, Heesom KJ & Stephens DJ Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function. Elife 7, e39655 (2018). 30320547 PMC6211827
  46. [50]Jensen VL Role for intraflagellar transport in building a functional transition zone. EMBO reports 19, e45862 (2018). 30429209 PMC6280794
  47. [51]Dharmat R SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium. J Cell Biol 217, 2851– 2865 (2018). 29899041 PMC6080925
  48. [52]Wiegering A Cell type‐specific regulation of ciliary transition zone assembly in vertebrates. The EMBO Journal 37, e97791 (2018). 29650680 PMC5978567
  49. [53]Jana SC Differential regulation of transition zone and centriole proteins contributes to ciliary base diversity. Nat. Cell Biol 20, 928– 941 (2018). 30013109
  50. [54]Lewis WR Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone. The FASEB Journal 33, 1440– 1455 (2018). 30133325 PMC6355093
  51. [55]Jensen VL Formation of the transition zone by Mks5/Rpgrip1L establishes a ciliary zone of exclusion (CIZE) that compartmentalises ciliary signalling proteins and controls PIP2 ciliary abundance. The EMBO Journal 34, 2537– 2556 (2015). 26392567 PMC4609185
  52. [56]Williams CL MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell Biol 192, 1023– 1041 (2011). 21422230 PMC3063147
  53. [57]Yee LE Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling. PLoS genetics 11, e1005627 (2015). 26540106 PMC4635004
  54. [58]Roberson EC TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J. Cell Biol 209, 129– 142 (2015). 25869670 PMC4395494
  55. [59]Milenkovic L Single-molecule imaging of Hedgehog pathway protein Smoothened in primary cilia reveals binding events regulated by Patched1. Proc Natl Acad Sci U S A 112, 8320– 8325 (2015). 26100903 PMC4500289
  56. [60]Shi X Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome. Nat. Cell Biol 19, 1178– 1188 (2017). 28846093 PMC5695680
  57. [61]Tanos BE Centriole distal appendages promote membrane docking, leading to cilia initiation. Genes Dev 27, 163– 8 (2013). 23348840 PMC3566309
  58. [62]Li W Centriole translocation and degeneration during ciliogenesis in Caenorhabditis elegans neurons. EMBO J 36, 2553– 2566 (2017). 28743734 PMC5579362
  59. [63]Nechipurenko IV, Berciu C, Sengupta P & Nicastro D Centriolar remodeling underlies basal body maturation during ciliogenesis in Caenorhabditis elegans. Elife 6, e25686 (2017). 28411364 PMC5392363
  60. [64]Serwas D, Su TY, Roessler M, Wang S & Dammermann A Centrioles initiate cilia assembly but are dispensable for maturation and maintenance in C. elegans. J. Cell Biol 216, 1659– 1671 (2017). 28411189 PMC5461022
  61. [65]Sugimoto M The keratin-binding protein Albatross regulates polarization of epithelial cells. The Journal of Cell Biology 183, 19– 28 (2008). 18838552 PMC2557036
  62. [66]Sang L Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145, 513– 528 (2011). 21565611 PMC3383065
  63. [67]Delous M Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6. Hum Mol Genet 18, 4711– 4723 (2009). 19755384 PMC2778369
  64. [68]Wei Q The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate. Nature Communications 7, 12437 (2016). PMC4992140 27534274
  65. [69]DeCaen PG, Delling M, Vien TN & Clapham DE Direct recording and molecular identification of the calcium channel of primary cilia. Nature 504, 315– 318 (2013). 24336289 PMC4073646
  66. [70]Delling M, DeCaen PG, Doerner JF, Febvay S & Clapham DE Primary cilia are specialized calcium signalling organelles. Nature 504, 311– 314 (2013). 24336288 PMC4112737
  67. [71]Borisy FF Calcium/calmodulin-activated phosphodiesterase expressed in olfactory receptor neurons. J. Neurosci 12, 915– 923 (1992). 1312138 PMC6576063
  68. [72]Mukherjee S A novel biosensor to study cAMP dynamics in cilia and flagella. eLife 5, e14052 (2016). 27003291 PMC4811770
  69. [73]Moore BS Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics. Proc Natl Acad Sci U S A 113, 13069– 13074 (2016). 27799542 PMC5135322
  70. [75]Saeed S Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nat. Genet 50, 175– 179 (2018). 29311637
  71. [76]Rees S Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease. J. Am. Soc. Nephrol 25, 232– 237 (2014). 24158982 PMC3904559
  72. [78]Breslow DK A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies. Nat. Genet 50, 460– 471 (2018). 29459677 PMC5862771
  73. [79]Pusapati GV CRISPR Screens Uncover Genes that Regulate Target Cell Sensitivity to the Morphogen Sonic Hedgehog. Dev. Cell 44, 113– 129.e8 (2018). 29290584 PMC5792066
  74. [80]Vuolo L, Herrera A, Torroba B, Menendez A & Pons S Ciliary adenylyl cyclases control the Hedgehog pathway. Journal of Cell Science 128, 2928– 2937 (2015). 26092933
  75. [81]Kwon RY, Temiyasathit S, Tummala P, Quah CC & Jacobs CR Primary cilium-dependent mechanosensing is mediated by adenylyl cyclase 6 and cyclic AMP in bone cells. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology 24, 2859– 2868 (2010). 20371630 PMC2909282
  76. [83]Hilgendorf KI, Johnson CT & Jackson PK The primary cilium as a cellular receiver: organizing ciliary GPCR signaling. Current Opinion in Cell Biology 39, 84– 92 (2016). 26926036 PMC4828300
  77. [84]Pedersen LB, Geimer S, Sloboda RD & Rosenbaum JL The Microtubule plus end-tracking protein EB1 is localized to the flagellar tip and basal bodies in Chlamydomonas reinhardtii. Current biology: CB 13, 1969– 1974 (2003). 14614822
  78. [85]Harris JA, Liu Y, Yang P, Kner P & Lechtreck KF Single-particle imaging reveals intraflagellar transport-independent transport and accumulation of EB1 in Chlamydomonas flagella. Molecular Biology of the Cell 27, 295– 307 (2016). 26631555 PMC4713132
  79. [87]Garcia-Gonzalo FR Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling. Dev. Cell 34, 400– 409 (2015). 26305592 PMC4557815 References 86– 87 demonstrate that the lipid PtdIns(4)P is enriched in the ciliary membrane thanks to the phosphatase INPP5E, which converts PtdIns(4,5)P2 into PtdIns(4)P
  80. [88]Poo M & Cone RA Lateral diffusion of rhodopsin in the photoreceptor membrane. Nature 247, 438– 441 (1974). 4818543
  81. [89]Aveldaño MI & Bazán NG Molecular species of phosphatidylcholine, -ethanolamine, -serine, and -inositol in microsomal and photoreceptor membranes of bovine retina. J Lipid Res 24, 620– 627 (1983). 6875386
  82. [90]Boesze-Battaglia K & Schimmel R Cell membrane lipid composition and distribution: implications for cell function and lessons learned from photoreceptors and platelets. J. Exp. Biol 200, 2927– 2936 (1997). 9359876
  83. [91]Andrews D & Nelson DL Biochemical studies of the excitable membrane of Paramecium tetraurelia. II. Phospholipids of ciliary and other membranes. Biochimica et biophysica acta 550, 174– 187 (1979). 758943
  84. [92]Chailley B & Boisvieux-Ulrich E Detection of plasma membrane cholesterol by filipin during microvillogenesis and ciliogenesis in quail oviduct. The journal of histochemistry and cytochemistry: official journal of the Histochemistry Society 33, 1– 10 (1985). 3965567
  85. [93]Lobasso S Lipidomic analysis of porcine olfactory epithelial membranes and cilia. Lipids 45, 593– 602 (2010). 20512424
  86. [94]Montesano R Inhomogeneous distribution of filipin-sterol complexes in the ciliary membrane of rat tracheal epithelium. Am. J. Anat 156, 139– 145 (1979). 517447
  87. [97]Souto-Padrón T & de Souza W Freeze-fracture localization of filipin-cholesterol complexes in the plasma membrane of Trypanosoma cruzi. The Journal of parasitology 69, 129– 137 (1983). 6402578
  88. [98]Tyler KM Flagellar membrane localization via association with lipid rafts. Journal of Cell Science 122, 859– 866 (2009). 19240119 PMC2714428
  89. [99]Emmer BT, Maric D & Engman DM Molecular mechanisms of protein and lipid targeting to ciliary membranes. Journal of Cell Science 123, 529– 536 (2010). 20145001 PMC2818192
  90. [100]Nachury MV, Seeley ES & Jin H Trafficking to the ciliary membrane: how to get across the periciliary diffusion barrier? Annual review of cell and developmental biology 26, 59– 87 (2010). PMC2952038 19575670
  91. [101]Serricchio M Flagellar membranes are rich in raft-forming phospholipids. Biology Open 4, 1143– 1153 (2015). 26276100 PMC4582118
  92. [102]Nguyen PAT, Liou W, Hall DH & Leroux MR Ciliopathy proteins establish a bipartite signaling compartment in a C. elegans thermosensory neuron. Journal of Cell Science 127, 5317– 5330 (2014). 25335890 PMC4265742
  93. [103]Schou KB KIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling. Nature Communications 8, 14177 (2017). PMC5290278 28134340 This study demonstrates cholesterol-dependent localization of the cholesterol-binding protein caveolin to the transition zone, which suggests a specialized lipid organization at the transition zone.
  94. [104]Kamiya R & Witman GB Submicromolar levels of calcium control the balance of beating between the two flagella in demembranated models of Chlamydomonas. J. Cell Biol 98, 97– 107 (1984). 6707098 PMC2112995
  95. [105]Lechtreck KF IFT–Cargo Interactions and Protein Transport in Cilia. Trends in Biochemical Sciences 40, 765– 778 (2015). 26498262 PMC4661101
  96. [106]Nachury MV The molecular machines that traffic signaling receptors into and out of cilia. Current Opinion in Cell Biology 51, 124– 131 (2018). 29579578 PMC5949257
  97. [107]Nakayama K & Katoh Y Ciliary protein trafficking mediated by IFT and BBSome complexes with the aid of kinesin-2 and dynein-2 motors. J. Biochem 163, 155– 164 (2018). 29272450
  98. [108]Bhogaraju S Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. Science (New York, NY) 341, 1009– 1012 (2013). PMC4359902 23990561
  99. [109]Craft JM, Harris JA, Hyman S, Kner P & Lechtreck KF Tubulin transport by IFT is upregulated during ciliary growth by a cilium-autonomous mechanism. The Journal of Cell Biology 208, 223– 237 (2015). 25583998 PMC4298693
  100. [110]Kubo T Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin. Journal of Cell Science 129, 2106– 2119 (2016). 27068536 PMC5506485
  101. [111]Taschner M, Mourão A, Awasthi M, Basquin J & Lorentzen E Structural basis of outer dynein arm intraflagellar transport by the transport adaptor protein ODA16 and the intraflagellar transport protein IFT46. J. Biol. Chem 292, 7462– 7473 (2017). 28298440 PMC5418046
  102. [112]Hou Y, Witman GB & Marshall W The N-terminus of IFT46 mediates intraflagellar transport of outer arm dynein and its cargo-adaptor ODA16. MBoC 28, 2420– 2433 (2017). 28701346 PMC5576905
  103. [113]Hunter EL The IDA3 adapter, required for intraflagellar transport of I1 dynein, is regulated by ciliary length. Molecular Biology of the Cell 29, 886– 896 (2018). 29467251 PMC5896928
  104. [114]Ye F Single molecule imaging reveals a major role for diffusion in the exploration of ciliary space by signaling receptors. eLife 2, e00654 (2013). 23930224 PMC3736543
  105. [115]Craft JM, Harris JA, Hyman S, Kner P & Lechtreck KF Tubulin transport by IFT is upregulated during ciliary growth by a cilium-autonomous mechanism. The Journal of Cell Biology 208, 223– 237 (2015). 25583998 PMC4298693
  106. [116]Milenkovic L Single-molecule imaging of Hedgehog pathway protein Smoothened in primary cilia reveals binding events regulated by Patched1. Proc Natl Acad Sci U S A 112, 8320– 8325 (2015). 26100903 PMC4500289
  107. [117]Monis WJ, Faundez V & Pazour GJ BLOC-1 is required for selective membrane protein trafficking from endosomes to primary cilia. J Cell Biol 216, 2131– 2150 (2017). 28576874 PMC5496619
  108. [118]Morthorst SK, Christensen ST & Pedersen LB Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins. The FEBS Journal 285, 4535– 4564 (2018). 29894023
  109. [119]Blacque OE, Scheidel N & Kuhns S Rab GTPases in cilium formation and function. Small GTPases 9, 76– 94 (2018). 29072526 PMC5902210
  110. [120]Brown JM, Cochran DA, Craige B, Kubo T & Witman GB Assembly of IFT Trains at the Ciliary Base Depends on IFT74. Current Biology 25, 1583– 1593 (2015). 26051893 PMC4482480
  111. [121]Deane JA, Cole DG, Seeley ES, Diener DR & Rosenbaum JL Localization of intraflagellar transport protein IFT52 identifies basal body transitional fibers as the docking site for IFT particles. Current biology: CB 11, 1586– 1590 (2001). 11676918
  112. [122]Wingfield JL IFT trains in different stages of assembly queue at the ciliary base for consecutive release into the cilium. eLife 6, e26609 (2017). 28562242 PMC5451262
  113. [123]Huang K, Diener DR, Mitchell A & Rosenbaum JL Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella. The Journal of Cell Biology 179, 501– 514 (2007). 17984324 PMC2064795
  114. [124]Brear AG, Yoon J, Wojtyniak M & Sengupta P Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia. Genetics 197, 667– 684 (2014). 24646679 PMC4063923
  115. [125]Bae YK General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia. Development 133, 3859– 70 (2006). 16943275
  116. [126]Dwyer ND, Adler CE, Crump JG, L’Etoile ND & Bargmann CI Polarized dendritic transport and the AP-1 mu1 clathrin adaptor UNC-101 localize odorant receptors to olfactory cilia. Neuron 31, 277– 87 (2001). 11502258
  117. [127]Eguether T, Cordelieres FP & Pazour GJ Intraflagellar transport is deeply integrated in hedgehog signaling. Mol. Biol. Cell 29, 1178– 1189 (2018). 29540531 PMC5935068
  118. [128]Liu P & Lechtreck KF The Bardet–Biedl syndrome protein complex is an adapter expanding the cargo range of intraflagellar transport trains for ciliary export. PNAS 115, E934– E943 (2018). 29339469 PMC5798339
  119. [130]Fu W, Wang L, Kim S, Li J & Dynlacht BD Role for the IFT-A Complex in Selective Transport to the Primary Cilium. Cell reports 17, 1505– 1517 (2016). 27806291 PMC5123888
  120. [131]Hirano T, Katoh Y & Nakayama K Intraflagellar transport-A complex mediates ciliary entry and retrograde trafficking of ciliary G protein-coupled receptors. Molecular Biology of the Cell 28, 429– 439 (2017). 27932497 PMC5341726
  121. [133]Picariello T A global analysis of IFT-A function reveals specialization for transport of membrane-associated proteins into cilia. J Cell Sci jcs.220749 (2019). doi: 10.1242/jcs.220749 PMC6382014 30659111 · DOI
  122. [134]Sun X Tubby is required for trafficking G protein-coupled receptors to neuronal cilia. Cilia 1, 21 (2012). 23351594 PMC3599646
  123. [135]Oswald F, Prevo B, Acar S & Peterman EJG Interplay between Ciliary Ultrastructure and IFT-Train Dynamics Revealed by Single-Molecule Super-resolution Imaging. Cell Rep 25, 224– 235 (2018). 30282031
  124. [136]Yang T, Tran MNT, Chong WM, Huang C-E & Liao J-C Intraflagellar transport proteins undergo nonaxonemal staged hindrance between the recruiting distal appendages and the cilium. bioRxiv 227587 (2017). doi: 10.1101/227587 · DOI
  125. [137]Kanie T The CEP19-RABL2 GTPase Complex Binds IFT-B to Initiate Intraflagellar Transport at the Ciliary Base. Dev. Cell 42, 22– 36.e12 (2017). 28625565 PMC5556974
  126. [138]Nishijima Y RABL2 interacts with the intraflagellar transport-B complex and CEP19 and participates in ciliary assembly. Molecular Biology of the Cell 28, 1652– 1666 (2017). 28428259 PMC5469608
  127. [139]Park J dTULP, the Drosophila melanogaster Homolog of Tubby, Regulates Transient Receptor Potential Channel Localization in Cilia. PLoS Genetics 9, e1003814 (2013). 24068974 PMC3778012
  128. [140]Park J Ciliary Phosphoinositide Regulates Ciliary Protein Trafficking in Drosophila. Cell Reports 13, 2808– 2816 (2015). 26723017
  129. [142]Ismail SA Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. The EMBO Journal 31, 4085– 4094 (2012). 22960633 PMC3474929
  130. [143]Wright KJ An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes & development 25, 2347– 2360 (2011). 22085962 PMC3222901
  131. [144]Zhang H UNC119 is required for G protein trafficking in sensory neurons. Nature neuroscience 14, 874– 880 (2011). 21642972 PMC3178889 References 141– 144 described the myristoyl shuttle UNC119 and the farnesyl shuttle PDE6δ and the release of their cargoes by ARL3–GTP inside cilia as a cogent mechanism of ciliary import of lipidated proteins.
  132. [145]Jensen VL & Leroux MR Gates for soluble and membrane proteins, and two trafficking systems (IFT and LIFT), establish a dynamic ciliary signaling compartment. Current Opinion in Cell Biology 47, 83– 91 (2017). 28432921
  133. [146]Stephen LA & Ismail S Shuttling and sorting lipid-modified cargo into the cilia. Biochemical Society Transactions 44, 1273– 1280 (2016). 27911709
  134. [147]Evans RJ The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium. Hum. Mol. Genet 19, 1358– 1367 (2010). 20106869
  135. [148]Blacque OE Functional genomics of the cilium, a sensory organelle. Current biology: CB 15, 935– 941 (2005). 15916950
  136. [149]Stephan A, Vaughan S, Shaw MK, Gull K & McKean PG An essential quality control mechanism at the eukaryotic Basal body prior to intraflagellar transport. Traffic (Copenhagen, Denmark) 8, 1323– 1330 (2007). 17645436
  137. [150]Gotthardt K A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins. eLife 4, e11859 (2015). 26551564 PMC4868535
  138. [151]Ivanova AA Biochemical characterization of purified mammalian ARL13B protein indicates that it is an atypical GTPase and ARL3 guanine nucleotide exchange factor (GEF). J. Biol. Chem 292, 11091– 11108 (2017). 28487361 PMC5491791
  139. [152]Zhang Q GTP-binding of ARL-3 is activated by ARL-13 as a GEF and stabilized by UNC-119. Scientific reports 6, 24534 (2016). 27102355 PMC4840320
  140. [153]Fansa EK, Kösling SK, Zent E, Wittinghofer A & Ismail S PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nature Communications 7, 11366 (2016). PMC5512577 27063844
  141. [154]Hurd T The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate development. Human Molecular Genetics 19, 4330– 4344 (2010). 20729296 PMC2957320
  142. [155]Humbert MC ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proceedings of the National Academy of Sciences 109, 19691– 19696 (2012). PMC3511769 23150559
  143. [156]Revenkova E, Liu Q, Gusella GL & Iomini C The Joubert syndrome protein ARL13B binds tubulin to maintain uniform distribution of proteins along the ciliary membrane. Journal of Cell Science 131, jcs212324 (2018). 29592971 PMC5992585
  144. [157]Nozaki S Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E. Journal of Cell Science 130, 563– 576 (2017). 27927754
  145. [159]Roy K Palmitoylation of the ciliary GTPase ARL13b is necessary for its stability and its role in cilia formation. Journal of Biological Chemistry 292, 17703– 17717 (2017). 28848045 PMC5663873
  146. [160]Cevik S Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans. The Journal of Cell Biology 188, 953– 969 (2010). 20231383 PMC2845074
  147. [161]Li Y, Wei Q, Zhang Y, Ling K & Hu J The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis. The Journal of Cell Biology 189, 1039– 1051 (2010). 20530210 PMC2886347
  148. [162]Mick DU Proteomics of Primary Cilia by Proximity Labeling. Developmental Cell 35, 497– 512 (2015). 26585297 PMC4662609
  149. [163]Viau A Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney. EMBO J 37, (2018). PMC6068446 29925518
  150. [164]Emmer BT Identification of a palmitoyl acyltransferase required for protein sorting to the flagellar membrane. Journal of Cell Science 122, 867– 874 (2009). 19240115 PMC2714429
  151. [165]Follit JA, Li L, Vucica Y & Pazour GJ The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. The Journal of Cell Biology 188, 21– 28 (2010). 20048263 PMC2812845
  152. [166]Goodwin JS Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway. J. Cell Biol 170, 261– 272 (2005). 16027222 PMC2171405
  153. [167]Rocks O An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307, 1746– 1752 (2005). 15705808
  154. [168]Huang K, Diener DR & Rosenbaum JL The ubiquitin conjugation system is involved in the disassembly of cilia and flagella. The Journal of Cell Biology 186, 601– 613 (2009). 19704024 PMC2733750
  155. [169]Green JA Recruitment of β-Arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization. Molecular and Cellular Biology 36, 223– 235 (2015). 26503786 PMC4702597
  156. [171]Datta P Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome. Proc Natl Acad Sci U S A 112, E4400– 9 (2015). 26216965 PMC4538681
  157. [173]Lechtreck KF Cycling of the signaling protein phospholipase D through cilia requires the BBSome only for the export phase. The Journal of Cell Biology 201, 249– 261 (2013). 23589493 PMC3628507
  158. [174]Eguether T IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Developmental Cell 31, 279– 290 (2014). 25446516 PMC4254547
  159. [175]Liew GM The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Developmental Cell 31, 265– 278 (2014). 25443296 PMC4255629
  160. [176]Jin H The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141, 1208– 1219 (2010). 20603001 PMC2898735
  161. [177]Klink BU A recombinant BBSome core complex and how it interacts with ciliary cargo. eLife 6, e27434 (2017). 29168691 PMC5700813
  162. [178]Baker SA The outer segment serves as a default destination for the trafficking of membrane proteins in photoreceptors. The Journal of Cell Biology 183, 485– 498 (2008). 18981232 PMC2575789
  163. [179]Ocbina PJR & Anderson KV Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Developmental dynamics 237, 2030– 2038 (2008). 18488998 PMC2702862
  164. [180]Zhang Q Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes. Proc Natl Acad Sci U S A 108, 20678– 20683 (2011). 22139371 PMC3251145
  165. [181]Trimble WS & Grinstein S Barriers to the free diffusion of proteins and lipids in the plasma membrane. The Journal of Cell Biology 208, 259– 271 (2015). 25646084 PMC4315255
  166. [182]Schmidt HB & Görlich D Transport Selectivity of Nuclear Pores, Phase Separation, and Membraneless Organelles. Trends Biochem. Sci 41, 46– 61 (2016). 26705895
  167. [183]Papermaster DS, Schneider BG & Besharse JC Vesicular transport of newly synthesized opsin from the Golgi apparatus toward the rod outer segment. Ultrastructural immunocytochemical and autoradiographic evidence in Xenopus retinas. Investigative ophthalmology & visual science 26, 1386– 1404 (1985). 2931395
  168. [184]Pedersen LB, Mogensen JB & Christensen ST Endocytic Control of Cellular Signaling at the Primary Cilium. Trends in Biochemical Sciences 41, 784– 797 (2016). 27364476
  169. [185]Benmerah A The ciliary pocket. Current Opinion in Cell Biology 25, 78– 84 (2013). 23153502
  170. [186]Langousis G Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei. Proc Natl Acad Sci U S A 113, 632– 637 (2016). 26721397 PMC4725476
  171. [187]Lobingier BT & von Zastrow M When trafficking and signaling mix: How subcellular location shapes G protein-coupled receptor activation of heterotrimeric G proteins. Traffic 20, 130– 136 (2019). 30578610 PMC6387827
  172. [188]Pan BT, Teng K, Wu C, Adam M & Johnstone RM Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. The Journal of Cell Biology 101, 942– 948 (1985). 2993317 PMC2113705
  173. [189]Von Bartheld CS & Altick AL Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Progress in neurobiology 93, 313– 340 (2011). 21216273 PMC3055956
  174. [190]Besharse JC, Hollyfield JG & Rayborn ME Turnover of rod photoreceptor outer segments. II. Membrane addition and loss in relationship to light. The Journal of Cell Biology 75, 507– 527 (1977). 264121 PMC2109927
  175. [191]Young RW & Bok D Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42, 392– 403 (1969). 5792328 PMC2107669
  176. [192]Salinas RY Photoreceptor discs form through peripherin-dependent suppression of ciliary ectosome release. The Journal of Cell Biology 216, 1489– 1499 (2017). 28381413 PMC5412563 This paper provides an in vivo demonstration of a role for ciliary ectocytosis in disposing of excess membranes. Ectocytosis must hence be suppressed for the formation of fresh disks in photoreceptor outer segments.
  177. [194]Loktev AV & Jackson PK Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell reports 5, 1316– 1329 (2013). 24316073
  178. [195]Marion S, Oakley RH, Kim K-M, Caron MG & Barak LS A beta-arrestin binding determinant common to the second intracellular loops of rhodopsin family G protein-coupled receptors. The Journal of biological chemistry 281, 2932– 2938 (2006). 16319069
  179. [196]van Dam TJP Evolution of modular intraflagellar transport from a coatomer-like progenitor. Proc Natl Acad Sci U S A 110, 6943– 6948 (2013). 23569277 PMC3637775
  180. [197]Shida T, Cueva JG, Xu Z, Goodman MB & Nachury MV The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient mechanosensation. Proc Natl Acad Sci U S A 107, 21517– 21522 (2010). 21068373 PMC3003046
  181. [198]Dentler W A Role for the Membrane in Regulating Chlamydomonas Flagellar Length. PLoS ONE 8, e53366 (2013). 23359798 PMC3554728
  182. [199]Rajagopalan V, Subramanian A, Wilkes DE, Pennock DG & Asai DJ Dynein-2 affects the regulation of ciliary length but is not required for ciliogenesis in Tetrahymena thermophila. Molecular Biology of the Cell 20, 708– 720 (2009). 19019986 PMC2626569
  183. [200]Hao L, Efimenko E, Swoboda P & Scholey JM The retrograde IFT machinery of C. elegans cilia: two IFT dynein complexes? PLoS One 6, e20995 (2011). 21695221 PMC3112216
  184. [201]Ocbina PJR, Eggenschwiler JT, Moskowitz I & Anderson KV Complex interactions between genes controlling trafficking in primary cilia. Nat. Genet 43, 547– 553 (2011). 21552265 PMC3132150
  185. [202]Das RM & Storey KG Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science (New York, NY) 343, 200– 204 (2014). PMC4066580 24408437
  186. [203]Mirvis M, Siemers KA, Nelson WJ & Stearns T Heterogeneous Dynamics and Mechanisms of Primary Cilium Disassembly in Mammalian Cells. bioRxiv 433144 (2018). doi: 10.1101/433144 · DOI
  187. [204]van Niel G, D’Angelo G & Raposo G Shedding light on the cell biology of extracellular vesicles. Nature Reviews Molecular Cell Biology 19, 213– 228 (2018). 29339798
  188. [207]Szempruch AJ Extracellular Vesicles from Trypanosoma brucei Mediate Virulence Factor Transfer and Cause Host Anemia. Cell 164, 246– 257 (2016). 26771494 PMC4715261
  189. [208]Wang J C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr. Biol 24, 519– 525 (2014). 24530063 PMC4659354
  190. [209]Hurley JH ESCRTs are everywhere. The EMBO Journal 34, 2398– 2407 (2015). 26311197 PMC4601661
  191. [210]Diener DR, Lupetti P & Rosenbaum JL Proteomic analysis of isolated ciliary transition zones reveals the presence of ESCRT proteins. Current biology: CB 25, 379– 384 (2015). 25578910 PMC4318714
  192. [211]Mierzwa B & Gerlich DW Cytokinetic abscission: molecular mechanisms and temporal control. Dev. Cell 31, 525– 538 (2014). 25490264
  193. [212]Chiaruttini N Relaxation of Loaded ESCRT-III Spiral Springs Drives Membrane Deformation. Cell 163, 866– 879 (2015). 26522593 PMC4644223
  194. [213]Wollert T, Wunder C, Lippincott-Schwartz J & Hurley JH Membrane scission by the ESCRT-III complex. Nature 458, 172– 177 (2009). 19234443 PMC2743992
  195. [214]Liu AP & Fletcher DA Actin Polymerization Serves as a Membrane Domain Switch in Model Lipid Bilayers. Biophysical Journal 91, 4064– 4070 (2006). 16963509 PMC1635687
  196. [215]Römer W Actin dynamics drive membrane reorganization and scission in clathrin-independent endocytosis. Cell 140, 540– 553 (2010). 20178746
  197. [216]Allain J-M, Storm C, Roux A, Amar MB & Joanny J-F Fission of a Multiphase Membrane Tube. Phys. Rev. Lett 93, 158104 (2004). 15524946
  198. [218]Pazour GJ Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Current biology: CB 12, R378– 80 (2002). 12062067
  199. [219]Yoder BK, Hou X & Guay-Woodford LM The Polycystic Kidney Disease Proteins, Polycystin-1, Polycystin-2, Polaris, and Cystin, Are Co-Localized in Renal Cilia. JASN 13, 2508– 2516 (2002). 12239239
  200. [220]Kleene SJ & Kleene NK The native TRPP2-dependent channel of murine renal primary cilia. Am. J. Physiol. Renal Physiol 312, F96– F108 (2017). 27760766 PMC5283891

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Authors
Nachury, M. V., & Mick, D. U.
Affiliations
  • University of California, San Francisco (US)
  • Saarland University (DE)
Corresponding author
Nachury, Maxence V.
ORCID
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2019-04-04
Volume
20
Issue
7
Pages
389-405
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/s41580-019-0116-4
PMC
PMC6738346
OpenAlex
W2934107946
Cited by
397
References
20
Citations by year
2026: 29 · 2025: 55 · 2024: 61 · 2023: 61 · 2022: 58 · 2021: 59 · 2020: 51 · 2019: 22 · 2014: 1
FWCI
6.46
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Eye Institute (P30EY002162)
  • National Institute of General Medical Sciences (R01GM089933)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Keywords
primary cilia, signal transduction, ciliary proteome, Hedgehog signaling, olfaction, phototransduction, cyclic AMP, sterols, extracellular vesicles
MeSH terms
Cyclic AMP, Animals, Cell Movement, Cilia, Humans, Second Messenger Systems, Proteome, Protein Transport

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