Anterograde Trafficking of Ciliary MAP Kinase-like ICK/CILK1 by the Intraflagellar Transport Machinery is Required for Intraciliary Retrograde Protein Trafficking

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2020 Aug 1

PMID 32732286

Citations 18

Authors

Kentaro Nakamura

Tatsuro Noguchi

Mariko Takahara

Yoshihiro Omori

Takahisa Furukawa

Yohei Katoh

Kazuhisa Nakayama

Affiliations

Soon will be listed here.

Abstract

ICK (also known as CILK1) is a mitogen-activated protein kinase-like kinase localized at the ciliary tip. Its deficiency is known to result in the elongation of cilia and causes ciliopathies in humans. However, little is known about how ICK is transported to the ciliary tip. We here show that the C-terminal noncatalytic region of ICK interacts with the intraflagellar transport (IFT)-B complex of the IFT machinery and participates in its transport to the ciliary tip. Furthermore, total internal reflection fluorescence microscopy demonstrated that ICK undergoes bidirectional movement within cilia, similarly to IFT particles. Analysis of knockout cells demonstrated that ICK deficiency severely impairs the retrograde trafficking of IFT particles and ciliary G protein-coupled receptors. In addition, we found that in knockout cells, ciliary proteins are accumulated at the bulged ciliary tip, which appeared to be torn off and released into the environment as an extracellular vesicle. The exogenous expression of various ICK constructs in knockout cells indicated that the IFT-dependent transport of ICK, as well as its kinase activity and phosphorylation at the canonical TDY motif, is essential for ICK function. Thus, we unequivocally show that ICK transported to the ciliary tip is required for retrograde ciliary protein trafficking and consequently for normal ciliary function.

Citing Articles

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References

Ishikawa H, Marshall W . Ciliogenesis: building the cell's antenna. Nat Rev Mol Cell Biol. 2011; 12(4):222-34. DOI: 10.1038/nrm3085. View

Mijalkovic J, van Krugten J, Oswald F, Acar S, Peterman E . Single-Molecule Turnarounds of Intraflagellar Transport at the C. elegans Ciliary Tip. Cell Rep. 2018; 25(7):1701-1707.e2. DOI: 10.1016/j.celrep.2018.10.050. View

Mukhopadhyay S, Rohatgi R . G-protein-coupled receptors, Hedgehog signaling and primary cilia. Semin Cell Dev Biol. 2014; 33:63-72. PMC: 4130902. DOI: 10.1016/j.semcdb.2014.05.002. View

Bhogaraju S, cajanek L, Fort C, Blisnick T, Weber K, Taschner M . Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. Science. 2013; 341(6149):1009-12. PMC: 4359902. DOI: 10.1126/science.1240985. View

Oh Y, Wang E, Gailey C, Brautigan D, Allen B, Fu Z . Ciliopathy-Associated Protein Kinase ICK Requires Its Non-Catalytic Carboxyl-Terminal Domain for Regulation of Ciliogenesis. Cells. 2019; 8(7). PMC: 6678984. DOI: 10.3390/cells8070677. View

Chen T, Wu D, Moskaluk C, Fu Z . Distinct expression patterns of ICK/MAK/MOK protein kinases in the intestine implicate functional diversity. PLoS One. 2013; 8(11):e79359. PMC: 3820702. DOI: 10.1371/journal.pone.0079359. View

Nishijima Y, Hagiya Y, Kubo T, Takei R, Katoh Y, Nakayama K . RABL2 interacts with the intraflagellar transport-B complex and CEP19 and participates in ciliary assembly. Mol Biol Cell. 2017; 28(12):1652-1666. PMC: 5469608. DOI: 10.1091/mbc.E17-01-0017. View

Taschner M, Mourao 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. 2017; 292(18):7462-7473. PMC: 5418046. DOI: 10.1074/jbc.M117.780155. View

Broekhuis J, Verhey K, Jansen G . Regulation of cilium length and intraflagellar transport by the RCK-kinases ICK and MOK in renal epithelial cells. PLoS One. 2014; 9(9):e108470. PMC: 4171540. DOI: 10.1371/journal.pone.0108470. View

10.

Wood C, Huang K, Diener D, Rosenbaum J . The cilium secretes bioactive ectosomes. Curr Biol. 2013; 23(10):906-11. PMC: 3850760. DOI: 10.1016/j.cub.2013.04.019. View

11.

Wang Y, Ren Y, Pan J . Regulation of flagellar assembly and length in by LF4, a MAPK-related kinase. FASEB J. 2019; 33(5):6431-6441. DOI: 10.1096/fj.201802375RR. View

12.

Omori Y, Chaya T, Katoh K, Kajimura N, Sato S, Muraoka K . Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival. Proc Natl Acad Sci U S A. 2010; 107(52):22671-6. PMC: 3012466. DOI: 10.1073/pnas.1009437108. View

13.

Nakayama K, Katoh Y . Architecture of the IFT ciliary trafficking machinery and interplay between its components. Crit Rev Biochem Mol Biol. 2020; 55(2):179-196. DOI: 10.1080/10409238.2020.1768206. View

14.

Larkins C, Aviles G, East M, Kahn R, Caspary T . Arl13b regulates ciliogenesis and the dynamic localization of Shh signaling proteins. Mol Biol Cell. 2011; 22(23):4694-703. PMC: 3226485. DOI: 10.1091/mbc.E10-12-0994. View

15.

Toropova K, Zalyte R, Mukhopadhyay A, Mladenov M, Carter A, Roberts A . Structure of the dynein-2 complex and its assembly with intraflagellar transport trains. Nat Struct Mol Biol. 2019; 26(9):823-829. PMC: 6774794. DOI: 10.1038/s41594-019-0286-y. View

16.

Briscoe J, Therond P . The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013; 14(7):416-29. DOI: 10.1038/nrm3598. View

17.

Haeussler M, Schonig K, Eckert H, Eschstruth A, Mianne J, Renaud J . Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol. 2016; 17(1):148. PMC: 4934014. DOI: 10.1186/s13059-016-1012-2. View

18.

Paige Taylor S, Bosakova M, Varecha M, Balek L, Barta T, Trantirek L . An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome. Hum Mol Genet. 2016; 25(18):3998-4011. PMC: 5291234. DOI: 10.1093/hmg/ddw240. View

19.

Okamoto S, Chaya T, Omori Y, Kuwahara R, Kubo S, Sakaguchi H . Ick Ciliary Kinase Is Essential for Planar Cell Polarity Formation in Inner Ear Hair Cells and Hearing Function. J Neurosci. 2017; 37(8):2073-2085. PMC: 6705687. DOI: 10.1523/JNEUROSCI.3067-16.2017. View

20.

Takahara M, Katoh Y, Nakamura K, Hirano T, Sugawa M, Tsurumi Y . Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis. Hum Mol Genet. 2017; 27(3):516-528. DOI: 10.1093/hmg/ddx421. View