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http://dx.doi.org/10.4062/biomolther.2015.025

Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells  

Shin, Ji Hyun (Graduate School of East-West Medical Science, Kyung Hee University)
Bae, Dong-Jun (ASAN Institute for Life Science, University of Ulsan College of Medicine, ASAN Medical Center)
Kim, Eun Sung (Graduate School of East-West Medical Science, Kyung Hee University)
Kim, Han Byeol (Graduate School of East-West Medical Science, Kyung Hee University)
Park, So Jung (Graduate School of East-West Medical Science, Kyung Hee University)
Jo, Yoon Kyung (Graduate School of East-West Medical Science, Kyung Hee University)
Jo, Doo Sin (Graduate School of East-West Medical Science, Kyung Hee University)
Jo, Dong-Gyu (The School of Pharmacy, Sungkyunkwan University)
Kim, Sang-Yeob (ASAN Institute for Life Science, University of Ulsan College of Medicine, ASAN Medical Center)
Cho, Dong-Hyung (Graduate School of East-West Medical Science, Kyung Hee University)
Publication Information
Biomolecules & Therapeutics / v.23, no.4, 2015 , pp. 327-332 More about this Journal
Abstract
Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic flux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.
Keywords
Mefloquine; Autophagy; Primary cilia; Retinal pigmented epithelial cells;
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1 Berbari, N. F., O'Connor, A. K., Haycraft, C. J. and Yoder, B. K. (2009) The primary cilium as a complex signaling center. Curr. Biol. 19, R526-R535.   DOI   ScienceOn
2 DiBella, L. M., Park, A. and Sun, Z. (2009) Zebrafi sh Tsc1 reveals functional interactions between the cilium and the TOR pathway. Hum. Mol. Genet. 18, 595-606.   DOI
3 Follit, J. A., Xu, F., Keady, B. T. and Pazour, G. J. (2009) Characterization of mouse IFT complex B. Cell Motil. Cytoskeleton 66, 457-468.   DOI
4 Gerdes, J. M. and Katsanis, N. (2008) Ciliary function and Wnt signal modulation. Curr. Top. Dev. Biol. 85, 175-195.   DOI
5 Goetz, S. C., and Anderson, K. V. (2010) The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331-344.   DOI   ScienceOn
6 Hao, L., Thein, M., Brust-Mascher, I., Civelekoglu-Scholey, G., Lu, Y., Acar, S., Prevo, B., Shaham, S. and Scholey, J. M. (2011) Intrafl agellar transport delivers tubulin isotypes to sensory cilium middle and distal segments. Nat. Cell Biol. 13, 790-798.   DOI
7 Hood, J. E., Jenkins, J. W., Milatovic, D., Rongzhu, L. and Aschner, M. (2010) Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons. Neurotoxicology 31, 518-523.   DOI
8 Huber, T. B., Edelstein, C. L., Hartleben, B., Inoki, K., Jiang, M., Koya, D., Kume, S., Lieberthal, W., Pallet, N., Quiroga, A., Ravichandran, K., Susztak, K., Yoshida, S. and Dong, Z. (2012) Emerging role of autophagy in kidney function, diseases and aging. Autophagy 8, 1009-1031.   DOI
9 Ishikawa, H. and Marshall, W. F. (2011) Ciliogenesis: building the cell's antenna. Nat. Rev. Mol. Cell Biol. 12, 222-234.   DOI
10 Janowsky, A., Eshleman, A. J., Johnson, R. A., Wolfrum, K. M., Hinrichs, D. J., Yang, J., Zabriskie, T. M., Smilkstein, M. J. and Riscoe, M.K. (2014) Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro. Psychopharmacology (Berl) 231, 2771-2783.   DOI
11 Klionsky, D. J. (2007) Autophagy : from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931-937.   DOI
12 Kim, J., Lee, J. E., Heynen-Genel, S., Suyama, E., Ono, K., Lee, K., Ideker, T., Aza-Blanc, P. and Gleeson, J. G. (2010) Functional genomic screen for modulators of ciliogenesis and cilium length. Nature 464, 1048-1051.   DOI   ScienceOn
13 Kim, J. I., Kim, J., Jang, H. S., Noh, M. R., Lipschutz, J. H. and Park, K. M. (2013) Reduction of oxidative stress during recovery accelerates normalization of primary cilia length that is altered after ischemic injury in murine kidneys. Am. J. Physiol. Renal. Physiol. 304, F1283-F1294.   DOI
14 Kiprilov, E. N., Awan, A., Desprat, R., Velho, M., Clement, C. A., Byskov, A. G., Andersen, C. Y., Satir, P., Bouhassira, E. E., Christensen, S. T. and Hirsch, R. E. (2008) Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery. J. Cell Biol. 180, 897-904.   DOI
15 Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R.T., Acevedo-Arozena, A., Adeli K, et al. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445-544.   DOI
16 Kroemer, G., Marino, G. and Levine, B. (2010) Autophagy and the integrated stress response. Mol. Cell 40, 280-293.   DOI
17 Lista P, Straface, E., Brunelleschi, S., Franconi, F. and Malorni, W. (2011) On the role of autophagy in human diseases: a gender perspective. J. Cell. Mol. Med. 15, 1443-1457.   DOI
18 Mizushima, N., Levine, B., Cuervo, A. M. and Klionsky, D. J. (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075.   DOI
19 Quinlan, R. J., Tobin, J. L. and Beales, P. L. (2008) Modeling ciliopathies: Primary cilia in development and disease. Curr. Top. Dev. Biol. 84, 249-310.   DOI
20 Pampliega, O., Orhon, I., Patel, B., Sridhar, S., Diaz-Carretero, A., Beau, I., Codogno, P., Satir, B. H., Satir, P. and Cuervo, A. M. (2013) Functional interaction between autophagy and ciliogenesis. Nature 502, 194-200.   DOI
21 Ravichandran, K. and Edelstein, C. L. (2014) Polycystic kidney disease: a case of suppressed autophagy? Semin. Nephrol. 34, 27-33.   DOI
22 Rubinsztein, D. C. (2006) The roles of intracellular protein-degradation pathway in neurodegeneration. Nature 443, 780-786.   DOI
23 Shin, J. H., Park, S. J., Kim, E. S., Jo, Y. K., Hong, J. and Cho, D.H. (2012a) Sertindole, a potent antagonist at dopamine $D_2$ receptors, induces autophagy by increasing reactive oxygen species in SHSY5Y neuroblastoma cells. Biol. Pharm. Bull. 35, 1069-1075.   DOI
24 Shin, J. H., Park, S. J., Jo, Y. K., Kim, E. S., Kang, H., Park, J. H., Lee, E. H. and Cho, D. H. (2012b) Suppression of autophagy exacerbates Mefloquine-mediated cell death. Neurosci. Lett. 515, 162-167.   DOI
25 Singla, V. and Reiter, J. F. (2006) The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313, 629-633.   DOI
26 Tang, Z., Lin, M. G., Stowe, T. R., Chen, S., Zhu, M., Stearns, T., Franco, B. and Zhong, Q. (2013) Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature 502, 254-257.   DOI
27 Toovey, S. (2009) Mefloquine neurotoxicity: a literature review. Travel Med. Infect. Dis. 7, 2-6.   DOI