1.
Malicki, J.J. & Johnson, C.A. The Cilium: Cellular Antenna and Central
Processing Unit. Trends Cell Biol 27, 126-140 (2017).
2.
Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L.B. & Christensen, S.T.
Cellular signalling by primary cilia in development, organ function and disease.
Nat Rev Nephrol 15, 199-219 (2019).
3.
Spasic, M. & Jacobs, C.R. Primary cilia: Cell and molecular mechanosensors
directing whole tissue function. Semin Cell Dev Biol 71, 42-52 (2017).
4.
Berbari, N.F., O'Connor, A.K., Haycraft, C.J. & Yoder, B.K. The primary cilium
as a complex signaling center. Curr Biol 19, R526-535 (2009).
5.
Tummala, P., Arnsdorf, E.J. & Jacobs, C.R. The Role of Primary Cilia in
Mesenchymal Stem Cell Differentiation: A Pivotal Switch in Guiding Lineage
Commitment. Cell Mol Bioeng 3, 207-212 (2010).
6.
Wheway, G., Nazlamova, L. & Hancock, J.T. Signaling through the Primary
Cilium. Front Cell Dev Biol 6, 8 (2018).
7.
Reiter, J.F. & Leroux, M.R. Genes and molecular pathways underpinning
ciliopathies. Nat Rev Mol Cell Biol 18, 533-547 (2017).
110
8.
Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N Engl J Med 364, 15331543 (2011).
9.
Nakatogawa, H. Mechanisms governing autophagosome biogenesis. Nat Rev Mol
Cell Biol 21, 439-458 (2020).
10.
Soreng, K., Neufeld, T.P. & Simonsen, A. Membrane Trafficking in Autophagy.
Int Rev Cell Mol Biol 336, 1-92 (2018).
11.
Gatica, D., Lahiri, V. & Klionsky, D.J. Cargo recognition and degradation by
selective autophagy. Nat Cell Biol 20, 233-242 (2018).
12.
Johansen, T. & Lamark, T. Selective Autophagy: ATG8 Family Proteins, LIR
Motifs and Cargo Receptors. J Mol Biol 432, 80-103 (2020).
13.
Gomes, L.C. & Dikic, I. Autophagy in antimicrobial immunity. Mol Cell 54, 224233 (2014).
14.
Palikaras, K., Lionaki, E. & Tavernarakis, N. Mechanisms of mitophagy in
cellular homeostasis, physiology and pathology. Nat Cell Biol 20, 1013-1022
(2018).
15.
Chino, H. & Mizushima, N. ER-Phagy: Quality Control and Turnover of
Endoplasmic Reticulum. Trends Cell Biol 30, 384-398 (2020).
16.
Anding, A.L. & Baehrecke, E.H. Cleaning House: Selective Autophagy of
111
Organelles. Dev Cell 41, 10-22 (2017).
17.
Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian
autophagy. Nat Rev Mol Cell Biol 19, 349-364 (2018).
18.
Mizushima, N., Levine, B. Autophagy in human diseases. N. Engl. J. Med. in press
19.
Mizushima, N. The ATG conjugation systems in autophagy. Curr Opin Cell Biol
63, 1-10 (2020).
20.
Birgisdottir, A.B., Lamark, T. & Johansen, T. The LIR motif - crucial for selective
autophagy. J Cell Sci 126, 3237-3247 (2013).
21.
Morleo, M. & Franco, B. The Autophagy-Cilia Axis: An Intricate Relationship.
Cells 8 (2019).
22.
Pampliega, O. & Cuervo, A.M. Autophagy and primary cilia: dual interplay. Curr
Opin Cell Biol 39, 1-7 (2016).
23.
Odabasi, E., Gul, S., Kavakli, I.H. & Firat-Karalar, E.N. Centriolar satellites are
required for efficient ciliogenesis and ciliary content regulation. EMBO Rep 20
(2019).
24.
Prosser, S.L. & Pelletier, L. Centriolar satellite biogenesis and function in
vertebrate cells. J Cell Sci 133 (2020).
25.
Ferrante, M.I. et al. Oral-facial-digital type I protein is required for primary cilia
112
formation and left-right axis specification. Nat Genet 38, 112-117 (2006).
26.
Singla, V., Romaguera-Ros, M., Garcia-Verdugo, J.M. & Reiter, J.F. Ofd1, a
human disease gene, regulates the length and distal structure of centrioles. Dev
Cell 18, 410-424 (2010).
27.
Tang, Z. et al. Autophagy promotes primary ciliogenesis by removing OFD1 from
centriolar satellites. Nature 502, 254-257 (2013).
28.
Liu, Z.Q. et al. Ciliogenesis is reciprocally regulated by PPARA and NR1H4/FXR
through controlling autophagy in vitro and in vivo. Autophagy 14, 1011-1027
(2018).
29.
Hsiao, C.J. et al. Gli2 modulates cell cycle re-entry through autophagy-mediated
regulation of the length of primary cilia. J Cell Sci 131 (2018).
30.
Wang, S., Livingston, M.J., Su, Y. & Dong, Z. Reciprocal regulation of cilia and
autophagy via the MTOR and proteasome pathways. Autophagy 11, 607-616
(2015).
31.
Kim, E.S. et al. Inhibition of autophagy suppresses sertraline-mediated primary
ciliogenesis in retinal pigment epithelium cells. PLoS One 10, e0118190 (2015).
32.
Pampliega, O. et al. Functional interaction between autophagy and ciliogenesis.
Nature 502, 194-200 (2013).
113
33.
Struchtrup, A., Wiegering, A., Stork, B., Ruther, U. & Gerhardt, C. The ciliary
protein RPGRIP1L governs autophagy independently of its proteasomeregulating function at the ciliary base in mouse embryonic fibroblasts. Autophagy
14, 567-583 (2018).
34.
Chino, H., Hatta, T., Natsume, T. & Mizushima, N. Intrinsically Disordered
Protein TEX264 Mediates ER-phagy. Mol Cell 74, 909-921 e906 (2019).
35.
Joachim, J. et al. Centriolar Satellites Control GABARAP Ubiquitination and
GABARAP-Mediated Autophagy. Curr Biol 27, 2123-2136 e2127 (2017).
36.
Behrends, C., Sowa, M.E., Gygi, S.P. & Harper, J.W. Network organization of the
human autophagy system. Nature 466, 68-76 (2010).
37.
Fry, A.M., Bayliss, R. & Roig, J. Mitotic Regulation by NEK Kinase Networks.
Front Cell Dev Biol 5, 102 (2017).
38.
Moniz, L., Dutt, P., Haider, N. & Stambolic, V. Nek family of kinases in cell cycle,
checkpoint control and cancer. Cell Div 6, 18 (2011).
39.
Cullati, S.N., Kabeche, L., Kettenbach, A.N. & Gerber, S.A. A bifurcated
signaling cascade of NIMA-related kinases controls distinct kinesins in anaphase.
J Cell Biol 216, 2339-2354 (2017).
40.
Eibes, S. et al. Nek9 Phosphorylation Defines a New Role for TPX2 in Eg5-
114
Dependent Centrosome Separation before Nuclear Envelope Breakdown. Curr
Biol 28, 121-129 e124 (2018).
41.
Roig, J., Mikhailov, A., Belham, C. & Avruch, J. Nercc1, a mammalian NIMAfamily kinase, binds the Ran GTPase and regulates mitotic progression. Genes
Dev 16, 1640-1658 (2002).
42.
Bertran, M.T. et al. Nek9 is a Plk1-activated kinase that controls early centrosome
separation through Nek6/7 and Eg5. EMBO J 30, 2634-2647 (2011).
43.
Upadhya, P., Birkenmeier, E.H., Birkenmeier, C.S. & Barker, J.E. Mutations in a
NIMA-related kinase gene, Nek1, cause pleiotropic effects including a
progressive polycystic kidney disease in mice. Proc Natl Acad Sci U S A 97, 217221 (2000).
44.
Otto, E.A. et al. NEK8 mutations affect ciliary and centrosomal localization and
may cause nephronophthisis. J Am Soc Nephrol 19, 587-592 (2008).
45.
Chivukula, R.R. et al. A human ciliopathy reveals essential functions for NEK10
in airway mucociliary clearance. Nat Med 26, 244-251 (2020).
46.
Casey, J.P. et al. Recessive NEK9 mutation causes a lethal skeletal dysplasia with
evidence of cell cycle and ciliary defects. Hum Mol Genet 25, 1824-1835 (2016).
47.
Shrestha, B.K. et al. NIMA-related kinase 9-mediated phosphorylation of the
115
microtubule-associated LC3B protein at Thr-50 suppresses selective autophagy of
p62/sequestosome 1. J Biol Chem 295, 1240-1260 (2020).
48.
Kalvari, I. et al. iLIR: A web resource for prediction of Atg8-family interacting
proteins. Autophagy 10, 913-925 (2014).
49.
Amemiya, C.T. et al. The African coelacanth genome provides insights into
tetrapod evolution. Nature 496, 311-316 (2013).
50.
Yoshii, S.R. et al. Systemic Analysis of Atg5-Null Mice Rescued from Neonatal
Lethality by Transgenic ATG5 Expression in Neurons. Dev Cell 39, 116-130
(2016).
51.
Natsume, T., Kiyomitsu, T., Saga, Y. & Kanemaki, M.T. Rapid Protein Depletion
in Human Cells by Auxin-Inducible Degron Tagging with Short Homology
Donors. Cell Rep 15, 210-218 (2016).
52.
Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through
Lkb1. Nat Cell Biol 12, 1115-1122 (2010).
53.
Orhon, I. et al. Primary-cilium-dependent autophagy controls epithelial cell
volume in response to fluid flow. Nat Cell Biol 18, 657-667 (2016).
54.
Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and
acute ischemic injury. J Am Soc Nephrol 22, 902-913 (2011).
116
55.
Pecci, A., Ma, X., Savoia, A. & Adelstein, R.S. MYH9: Structure, functions and
role of non-muscle myosin IIA in human disease. Gene 664, 152-167 (2018).
56.
Copeland, J. Actin-based regulation of ciliogenesis - The long and the short of it.
Semin Cell Dev Biol 102, 132-138 (2020).
57.
Wang, L. & Dynlacht, B.D. The regulation of cilium assembly and disassembly
in development and disease. Development 145 (2018).
58.
Kim, J. et al. Functional genomic screen for modulators of ciliogenesis and cilium
length. Nature 464, 1048-1051 (2010).
59.
Pitaval, A. et al. Microtubule stabilization drives 3D centrosome migration to
initiate primary ciliogenesis. J Cell Biol 216, 3713-3728 (2017).
60.
Cao, J. et al. miR-129-3p controls cilia assembly by regulating CP110 and actin
dynamics. Nat Cell Biol 14, 697-706 (2012).
61.
Kim, J. et al. Actin remodelling factors control ciliogenesis by regulating
YAP/TAZ activity and vesicle trafficking. Nat Commun 6, 6781 (2015).
62.
Yan, X. & Zhu, X. Branched F-actin as a negative regulator of cilia formation.
Exp Cell Res 319, 147-151 (2013).
63.
Shutova, M.S. & Svitkina, T.M. Mammalian nonmuscle myosin II comes in three
flavors. Biochem Biophys Res Commun 506, 394-402 (2018).
117
64.
Even-Ram, S. et al. Myosin IIA regulates cell motility and actomyosinmicrotubule crosstalk. Nat Cell Biol 9, 299-309 (2007).
65.
Vicente-Manzanares, M., Ma, X., Adelstein, R.S. & Horwitz, A.R. Non-muscle
myosin II takes centre stage in cell adhesion and migration. Nat Rev Mol Cell Biol
10, 778-790 (2009).
66.
Rao, Y., Hao, R., Wang, B. & Yao, T.P. A Mec17-Myosin II Effector Axis
Coordinates Microtubule Acetylation and Actin Dynamics to Control Primary
Cilium Biogenesis. PLoS One 9, e114087 (2014).
67.
Hong, H., Kim, J. & Kim, J. Myosin heavy chain 10 (MYH10) is required for
centriole migration during the biogenesis of primary cilia. Biochem Biophys Res
Commun 461, 180-185 (2015).
68.
Uhlen, M. et al. Proteomics. Tissue-based map of the human proteome. Science
347, 1260419 (2015).
69.
Fry, A.M., O'Regan, L., Sabir, S.R. & Bayliss, R. Cell cycle regulation by the NEK
family of protein kinases. J Cell Sci 125, 4423-4433 (2012).
70.
Wirth, M. et al. Molecular determinants regulating selective binding of autophagy
adapters and receptors to ATG8 proteins. Nat Commun 10, 2055 (2019).
71.
Finn, R.N., Chauvigne, F., Hlidberg, J.B., Cutler, C.P. & Cerda, J. The lineage-
118
specific evolution of aquaporin gene clusters facilitated tetrapod terrestrial
adaptation. PLoS One 9, e113686 (2014).
72.
Marra, A.N., Li, Y. & Wingert, R.A. Antennas of organ morphogenesis: the roles
of cilia in vertebrate kidney development. Genesis 54, 457-469 (2016).
73.
Kramer-Zucker, A.G. et al. Cilia-driven fluid flow in the zebrafish pronephros,
brain and Kupffer's vesicle is required for normal organogenesis. Development
132, 1907-1921 (2005).
74.
Gan, B. et al. Role of FIP200 in cardiac and liver development and its regulation
of TNFalpha and TSC-mTOR signaling pathways. J Cell Biol 175, 121-133
(2006).
75.
Sou, Y.S. et al. The Atg8 conjugation system is indispensable for proper
development of autophagic isolation membranes in mice. Mol Biol Cell 19, 47624775 (2008).
76.
Kaizuka, T. et al. An Autophagic Flux Probe that Releases an Internal Control.
Mol Cell 64, 835-849 (2016).
77.
Saitoh, T., Nakano, H., Yamamoto, N. & Yamaoka, S. Lymphotoxin-beta receptor
mediates NEMO-independent NF-kappaB activation. FEBS Lett 532, 45-51
(2002).
119
78.
Morita, K. et al. Genome-wide CRISPR screen identifies TMEM41B as a gene
required for autophagosome formation. J Cell Biol 217, 3817-3828 (2018).
79.
Hosokawa, N., Hara, Y. & Mizushima, N. Generation of cell lines with
tetracycline-regulated autophagy and a role for autophagy in controlling cell size.
FEBS Lett 580, 2623-2629 (2006).
80.
Dummer, A., Poelma, C., DeRuiter, M.C., Goumans, M.J. & Hierck, B.P.
Measuring the primary cilium length: improved method for unbiased highthroughput analysis. Cilia 5, 7 (2016).
81.
Schwanhausser, B. et al. Global quantification of mammalian gene expression
control. Nature 473, 337-342 (2011).
82.
Masuda, T., Tomita, M. & Ishihama, Y. Phase transfer surfactant-aided trypsin
digestion for membrane proteome analysis. J Proteome Res 7, 731-740 (2008).
83.
Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification,
enrichment, pre-fractionation and storage of peptides for proteomics using
StageTips. Nat Protoc 2, 1896-1906 (2007).
84.
Boersema, P.J., Raijmakers, R., Lemeer, S., Mohammed, S. & Heck, A.J.
Multiplex peptide stable isotope dimethyl labeling for quantitative proteomics.
Nat Protoc 4, 484-494 (2009).
120
85.
Kumar, S., Stecher, G., Li, M., Knyaz, C. & Tamura, K. MEGA X: Molecular
Evolutionary Genetics Analysis across Computing Platforms. Mol Biol Evol 35,
1547-1549 (2018).
86.
Singh, N., and Bhalla, N. Moonlighting Proteins. Annu Rev Genet 54, 265-285
(2020)
87.
Minoshima, Y., et al. Phosphorylation by aurora B converts MgcRacGAP to a
RhoGAP during cytokinesis. Dev Cell 4, 549-560 (2003).
121
Acknowledgments
I thank Professor Takahide Nagase for his mentorship and encouragement, Professor
Noboru Mizushima for showing me what a researcher is and how fascinating research
can be. I appreciate Haruka Chino for teaching me the basics of how to perform
experiments from scratch, Hayashi Yamamoto for constructive discussion, Saori Yoshii
for mouse sampling, Keiko Igarashi for help with histological examinations, Shoji
Yamaoka for pMRX-vector, Teruhito Yasui for pCG-VSV-G and pCG-gag-pol, Robert
A. Weinberg for pCMV-VSV-G, Didier Trono for psPAX2, and Keith Mostov for
pLKO.1-blast vector.
I would like to thank all lab members for helping me. Finally, I would like to express my
sincere gratitude to my wife and my two wonderful children for supporting me throughout
my research life.
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