An Overview of the Primary Cilium and RPGRIP1L: The Signalling Hub’s Anchor for Organ Development and Homeostasis
Keywords:cilia syndromes, ciliogenesis, ciliopathies, primary cilia, RPGRIP1L, transition zone
Research on the primary cilium has been growing exponentially in the past several decades due to its functions as a cell signalling hub, which defects leads to several disorders and abnormalities collectively known as ciliopathies. Among other parts of the primary cilium structures, the transition zone is the area whose defects lead to the most severe clinical manifestations and high lethality. The ciliary transition zone consists of multiple protein modules that are hypothesized to be anchored by the RPGRIP1L protein. Despite its importance, RPGRIP1L studies remain hidden from the limelight, and our understanding of the protein remains scattered. This review summarizes the clinical manifestations and molecular mechanisms of the RPGRIP1L in the primary cilium. We then take a closer look at each RPGRIP1L’s protein domain to understand how each domain ensures proper functions and localization of RPGRIP1L. The three domains of RPGRIP1L are postulated to be involved in different roles. While the coiled coil domain is vital for scaffolding the protein to the centriolar structure, the ability of the C2 domain to interact with lipid allows the formation of ‘lipid gate’ at the transition zone. The high variability of the RPGR interaction domain enable the RPGRIP1L to interact with multiple different proteins, making it an ideal anchor for other ciliary protein modules in the transition zone.
N. F. Berbari, A. K. O’Connor, C. J. Haycraft, and B. K. Yoder, “The Primary Cilium as a Complex Signaling Center,” Curr. Biol., vol. 19, no. 13, pp. R526–R535, 2009.
S. C. Goetz and K. V Anderson, “The primary cilium: a signalling centre during vertebrate development,” Nat. Rev. Genet., vol. 11, no. 5, pp. 331–344, 2010.
G. Wheway, L. Nazlamova, and J. T. Hancock, “Signaling through the Primary Cilium.,” Front. cell Dev. Biol., vol. 6, p. 8, 2018.
P. Satir, L. B. Pedersen, and S. T. Christensen, “The primary cilium at a glance,” J. Cell Sci., vol. 123, no. 4, pp. 499–503, 2010.
A. M. Waters and P. L. Beales, “Ciliopathies: An expanding disease spectrum,” Pediatr. Nephrol., vol. 26, no. 7, pp. 1039–1056, 2011.
L. Wang and B. D. Dynlacht, “The regulation of cilium assembly and disassembly in development and disease,” Dev., vol. 145, no. 18, 2018.
K. Szymanska and C. A. Johnson, “The transition zone: An essential functional compartment of cilia,” Cilia, vol. 1, no. 1, p. 1, 2012.
A. Dummer, C. Poelma, M. C. DeRuiter, M. J. T. H. Goumans, and B. P. Hierck, “Measuring the primary cilium length: Improved method for unbiased high-throughput analysis,” Cilia, vol. 5, no. 1, pp. 1–9, 2016.
P. Satir, “CILIA: before and after,” Cilia, vol. 6, no. 1, p. 1, 2017.
H. Lodish, A. Berk, S. L. Zipursky, P. Matsudaira, D. Baltimore, and J. Darnell, “Cilia and flagella: structure and movement,” Mol. Cell Biol., 2000.
I. Ibañez-Tallon, N. Heintz, and H. Omran, “To beat or not to beat: roles of cilia in development and disease,” Hum. Mol. Genet., vol. 12, no. suppl_1, pp. R27–R35, Apr. 2003.
D. Bray, Cell movements: from molecules to motility. Garland Science, 2000.
A. O. Kovalevskij, Entwickelungsgeschichte des Amphioxus lanceolatus, 11th ed. Memoires de l’Academie Imperiale des Sciences de St.-Petersbourg VII, 1867.
S. Sorokin, “Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells.,” J. Cell Biol., vol. 15, no. 10, pp. 363–377, 1962.
C. A. Poole, M. H. Flint, and B. W. Beaumont, “Analysis of the morphology and function of primary cilia in connective tissues: a cellular cybernetic probe?,” Cell Motil., vol. 5, no. 3, pp. 175–193, 1985.
G. Albrecht-Buehler and A. Bushnell, “The ultrastructure of primary cilia in quiescent 3T3 cells,” Exp. Cell Res., vol. 126, no. 2, pp. 427–437, 1980.
P. Satir and S. T. Christensen, “Overview of Structure and Function of Mammalian Cilia,” Annu. Rev. Physiol., vol. 69, no. 1, pp. 377–400, Feb. 2007.
G. M. W. Adams, B. Huang, G. Piperno, and D. J. L. Luck, “Central-pair microtubular complex of Chlamydomonas flagella: Polypeptide composition as revealed by analysis of mutants,” J. Cell Biol., vol. 91, no. 1, pp. 69–76, 1981.
S. O. Ann, “Molecular Motors,” Mol. Mot., vol. 422, no. April, pp. 759–765, 2007.
S. Nonaka et al., “Randomisation of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein,” Cell, vol. 95, no. 6, pp. 829–837, 1998.
L. E. Ostrowski et al., “A proteomic analysis of human cilia: identification of novel components.,” Mol. Cell. Proteomics, vol. 1, no. 6, pp. 451–465, 2002.
S. T. Christensen, C. A. Clement, P. Satir, and L. B. Pedersen, “Primary cilia and coordination of receptor tyrosine kinase (RTK) signalling,” J. Pathol., vol. 226, no. 2, pp. 172–184, 2012.
J. L. Badano, N. Mitsuma, P. L. Beales, and N. Katsanis, “The Ciliopathies: An Emerging Class of Human Genetic Disorders,” Annu. Rev. Genomics Hum. Genet., vol. 7, no. 1, pp. 125–148, 2006.
M. Adams, “The primary cilium: An orphan organelle finds a home,” Nat. Educ., vol. 3, no. 9, p. 54, 2010.
H. Ishikawa, J. Thompson, J. R. Yates, and W. F. Marshall, “Proteomic analysis of mammalian primary cilia,” Curr. Biol., vol. 22, no. 5, pp. 414–419, 2012.
V. Singla, “The Primary Cilium as the Cell’s Antenna: Signaling at a Sensory Organelle,” Science (80-. )., vol. 313, no. 5787, pp. 629–633, Aug. 2006.
K. G. Kozminski, K. A. Johnson, P. Forscher, and J. L. Rosenbaum, “A motility in the eukaryotic flagellum unrelated to flagellar beating.,” Proc. Natl. Acad. Sci., vol. 90, no. 12, pp. 5519–5523, 1993.
G. J. Pazour et al., “Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene Tg737, are required for assembly of cilia and flagella,” J. Cell Biol., vol. 151, no. 3, pp. 709–718, 2000.
S. Hoyer-Fender, “Centriole maturation and transformation to basal body,” Semin. Cell Dev. Biol., vol. 21, no. 2, pp. 142–147, 2010.
J. J. Malicki and C. A. Johnson, “The Cilium: Cellular Antenna and Central Processing Unit,” Trends Cell Biol., vol. 27, no. 2, pp. 126–140, 2017.
R. Uzbekov and I. Alieva, “Who are you, subdistal appendages of centriole?,” R. Soc. Open Sci., vol. 8, no. 7, 2018.
D. A. Hoey, M. E. Downs, and C. R. Jacobs, “The mechanics of the primary cilium: An intricate structure with complex function,” J. Biomech., vol. 45, no. 1, pp. 17–26, Jan. 2012.
A. Benmerah, “The ciliary pocket,” Curr. Opin. Cell Biol., vol. 25, no. 1, pp. 78–84, Feb. 2013.
F. R. Garcia-Gonzalo and J. F. Reiter, “Scoring a backstage pass: Mechanisms of ciliogenesis and ciliary access,” J. Cell Biol., vol. 197, no. 6, pp. 697–709, 2012.
H. Ishikawa and W. F. Marshall, “Ciliogenesis: Building the cell’s antenna,” Nat. Rev. Mol. Cell Biol., vol. 12, no. 4, pp. 222–234, 2011.
J. M. Berg, J. L. Tymoczko, and L. Stryer, “Kinesin and dynein move along microtubules,” Biochemistry, vol. 5, 2002.
P. G. Czarnecki and J. V. Shah, “The ciliary transition zone: from morphology and molecules to medicine,” Trends Cell Biol., vol. 22, no. 4, pp. 201–210, Apr. 2012.
R. G. W. Anderson, “The three-dimensional structure of the basal body from the rhesus monkey oviduct,” J. Cell Biol., vol. 54, no. 2, pp. 246–265, 1972.
S. Graser et al., “Cep164, a novel centriole appendage protein required for primary cilium formation,” J. Cell Biol., vol. 179, no. 2, pp. 321–330, 2007.
V. S. Gerasimchuk and A. A. Shitov, “The dynamics of domain walls in an easy-plane magnet in the field of an acoustic wave,” Phys. Solid State, vol. 45, no. 1, pp. 124–129, 2003.
J. A. Deane, D. G. Cole, E. S. Seeley, D. R. Diener, and J. L. Rosenbaum, “Localisation of intraflagellar transport protein IFT52 identifies basal body transitional fibers as the docking site for IFT particles,” Curr. Biol., vol. 11, no. 20, pp. 1586–1590, 2001.
I. R. Gibbsins and A. V. Grimstone, “On flagellar structure in certain flagellates.,” J. Biophys. Biochem. Cytol., vol. 7, no. 4, pp. 697–716, 1960.
N. B. Gilula and P. Satir, “The ciliary necklace a ciliary membrane specialisation,” J. Cell Biol., vol. 53, no. 2, pp. 494–509, 1972.
B. Craige et al., “CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content,” J. Cell Biol., vol. 190, no. 5, pp. 927–940, 2010.
C. L. Williams et al., “MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis,” J. Cell Biol., vol. 192, no. 6, pp. 1023–1041, 2011.
L. Sang et al., “Mapping the NPHP-JBTS-MKS Protein Network Reveals Ciliopathy Disease Genes and Pathways,” Cell, vol. 145, no. 4, pp. 513–528, May 2011.
D. Gogendeau et al., “MKS-NPHP module proteins control ciliary shedding at the transition zone,” PLoS Biol., vol. 18, no. 3, p. e3000640, 2020.
L. Huang 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., vol. 89, no. 6, pp. 713–730, Dec. 2011.
F. R. Garcia-Gonzalo et al., “A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition,” Nat. Genet., vol. 43, no. 8, pp. 776–784, 2011.
S. R. Patnaik, R. K. Raghupathy, X. Zhang, D. Mansfield, and X. Shu, “The Role of RPGR and Its Interacting Proteins in Ciliopathies,” J. Ophthalmol., vol. 2015, p. 414781, 2015.
M. Delous et al., “The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome,” Nat. Genet., vol. 39, no. 7, pp. 875–881, 2007.
H. H. Arts et al., “Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome,” Nat. Genet., vol. 39, no. 7, pp. 882–888, 2007.
C. Gerhardt et al., “The transition zone protein Rpgrip 1l regulates proteasomal activity at the primary cilium,” J. Cell Biol., vol. 210, no. 1, pp. 115–133, 2015.
B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter, “From RNA to protein,” in Molecular Biology of the Cell. 4th edition, Garland Science, 2002.
P. Zhou and J. Zhou, “The Primary Cilium as a Therapeutic Target in Ocular Diseases,” Front. Pharmacol., vol. 11, 2020.
Y. Zhao et al., “The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesis,” Proc. Natl. Acad. Sci., vol. 100, no. 7, pp. 3965–3970, 2003.
J. Won et al., “RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesis,” Hum. Mol. Genet., vol. 18, no. 22, pp. 4329–4339, 2009.
H. Shiwaku, A. Umino, M. Umino, and T. Nishikawa, “Phencyclidine-induced dysregulation of primary cilia in the rodent brain,” Brain Res., vol. 1674, pp. 62–69, Nov. 2017.
Schizophrenia Working Group of the Psychiatric Genomics Consortium, “Biological insights from 108 schizophrenia-associated genetic loci.,” Nature, vol. 511, no. 7510, pp. 421–7, Jul. 2014.
M. C. O’Donovan et al., “Identification of loci associated with schizophrenia by genome-wide association and follow-up.,” Nat. Genet., vol. 40, no. 9, pp. 1053–5, Sep. 2008.
Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address: email@example.com and Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, “Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes.,” Cell, vol. 173, no. 7, p. 1705–1715.e16, 2018.
E. Reble, Y. Feng, K. G. Wigg, and C. L. Barr, “DNA Variant in the RPGRIP1L Gene Influences Alternative Splicing,” Mol. Neuropsychiatry, vol. 5, no. 1, pp. 97–106, 2019.
A. Mahuzier et al., “Dishevelled stabilisation by the ciliopathy protein Rpgrip1l is essential for planar cell polarity,” J. Cell Biol., vol. 198, no. 5, pp. 927–940, 2012.
J. Vierkotten, R. Dildrop, T. Peters, B. Wang, and U. Rüther, “Ftm is a novel basal body protein of cilia involved in Shh signalling,” Development, vol. 134, no. 14, pp. 2569–2577, 2007.
A. R. Jauregui, K. C. Q. Nguyen, D. H. Hall, and M. M. Barr, “The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure,” J. Cell Biol., vol. 180, no. 5, pp. 973–988, 2008.
N. T. Gorden et al., “CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290,” Am. J. Hum. Genet., vol. 83, no. 5, pp. 559–571, 2008.
B. Chih et al., “A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain,” Nat. Cell Biol., vol. 14, no. 1, pp. 61–72, 2012.
U. Mayer et al., “The proteome of rat olfactory sensory cilia,” Proteomics, vol. 9, no. 2, pp. 322–334, 2009.
G. J. Pazour, N. Agrin, J. Leszyk, and G. B. Witman, “Proteomic analysis of a eukaryotic cilium,” J. Cell Biol., vol. 170, no. 1, pp. 103–113, 2005.
V. L. Jensen et al., “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,” EMBO J., vol. 34, no. 20, pp. 2537–2556, Oct. 2015.
A. Wiegering et al., “Cell type-specific regulation of ciliary transition zone assembly in vertebrates,” EMBO J., vol. 37, no. 10, p. e97791, May 2018.
Y. P. Liu et al., “Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators,” J. Clin. Invest., vol. 124, no. 5, pp. 2059–2070, 2014.
B. Wang, J. F. Fallon, and P. A. Beachy, “Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb,” Cell, vol. 100, no. 4, pp. 423–434, 2000.
C. Gerhardt, J. M. Lier, S. Kuschel, and U. Rüther, “The ciliary protein Ftm is required for ventricular wall and septal development,” PLoS One, vol. 8, no. 2, p. e57545, 2013.
L. Besse et al., “Primary cilia control telencephalic patterning and morphogenesis via Gli3 proteolytic processing,” Development, vol. 138, no. 10, pp. 2079–2088, 2011.
A. Inoko et al., “Trichoplein and Aurora A block aberrant primary cilia assembly in proliferating cells,” J. Cell Biol., vol. 197, no. 3, pp. 391–405, 2012.
K. Kasahara et al., “Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension,” Nat. Commun., vol. 5, pp. 1–10, 2014.
Z. Tang et al., “Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites,” Nature, vol. 502, no. 7470, pp. 254–257, 2013.
O. Pampliega et al., “Functional interaction between autophagy and ciliogenesis,” Nature, vol. 502, no. 7470, pp. 194–200, 2013.
A. Struchtrup, A. Wiegering, B. Stork, U. Rüther, and C. Gerhardt, “The ciliary protein RPGRIP1L governs autophagy independently of its proteasome-regulating function at the ciliary base in mouse embryonic fibroblasts,” Autophagy, vol. 14, no. 4, pp. 567–583, 2018.
T. P. Neufeld, “TOR-dependent control of autophagy: biting the hand that feeds,” Curr. Opin. Cell Biol., vol. 22, no. 2, pp. 157–168, Apr. 2010.
C. H. Jung, S. H. Ro, J. Cao, N. M. Otto, and D. H. Kim, “MTOR regulation of autophagy,” FEBS Lett., vol. 584, no. 7, pp. 1287–1295, 2010.
S. Wang, M. J. Livingston, Y. Su, and Z. Dong, “Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways,” Autophagy, vol. 11, no. 4, pp. 607–616, 2015.