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Atg5 plays crucial roles in naked mole-rat cell proliferation and maintenance of cellular homeostasis

Kim, Junhyeong 大阪大学 DOI:10.18910/77466

2020.06.19

概要

The naked mole-rat (NMR, heterocephalus glaber) is a eusocial subterranean rodent, native to Africa. NMRs are the longest-living rodent species with a maximum lifespan of over 30 years. While body size of NMRs is similar to that of house mouse (Mus musculus), NMRs live 10 times longer than house mouse. Furthermore, NMRs generally experience a greatly extended healthy lifespan within their total lifespan of 30 years. These extraordinary mammals also exhibit profound resistance to both spontaneous and experimentally induced cancer. A previous study identified that NMR fibroblasts exhibit hypersensitive contact inhibition termed early contact inhibition, which is regulated by p16INK4a, p53 and Rb pathways. Moreover, NMRs have increased levels of basal macroautophagy compared with mouse.

Macroautophagy (hereafter, autophagy) is the evolutionarily conserved pathway that degrades intracellular components, including aggregated protein, organelles, macromolecules and invading pathogens via lysosomal degradation. Autophagy contributes to the maintenance of cellular homeostasis and fitness in both basal state a stressed state. Previous studies have suggested that autophagy is deeply implicated in animal aging. Many species display decreased autophagy activity with age. Furthermore, Studies in C.elegans have suggested that autophagy activation is implicated in lifespan extension. Brain-specific overexpression of Atg8a and neuron-specific upregulation of Atg1 activate and extend the lifespan in Drosophila. Atg5 overexpression in mice contributes to activation of autophagy and extension of lifespan. However, molecular mechanisms underlying high basal autophagy activity of NMRs and its physiological significance of this phenomenon remain to be elucidated.

In this study, I identified that the Atg12-Atg5 conjugate, a critical component of autophagosome formation, was highly expressed in NMR skin fibroblasts (NSFs) compared with that in mouse skin fibroblasts. I then generated Atg5 knockdown NSFs via lentiviral shRNA vectors to investigate the role of Atg5 in NSFs. Phenotypic analysis of Atg5 knockdown NSFs revealed that high basal autophagy activity in NSFs was associated with abundant expression of the Atg12-Atg5 conjugate. Atg5 knockdown in NSFs led to accumulation of dysfunctional mitochondria, frequent appearance of abnormally large-sized cells, and suppressed cell proliferation and cell adhesion ability, promoting anoikis/apoptosis accompanied by upregulation of apoptosis-related genes, Bax and Noxa. Furthermore, inhibition of the p53/Rb pro-apoptotic pathway with SV40 large T antigen abolished the increase in cell size, cell cycle arrest and suppression of cell adhesion, the phenotypes related to anoikis/apoptosis induced by Atg5 knockdown. Taken together, these results suggest that high basal autophagy activity in NMR cells, mediated by Atg5, contribute to suppression of apoptosis by interfering with the activation of the p53/Rb pro-apoptotic pathway, potentially via degradation of stress-inducing factors. This mechanism could benefit the longevity of NMR cells.

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参考文献

Buffenstein, R. 2005. The naked mole-rat: A new long-living model for human aging research. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 60: 1369–1377.

Buffenstein, R. 2008. Negligible senescence in the longest living rodent, the naked mole-rat: Insights from a successfully aging species. Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology, 178: 439– 445.

Campisi, J. and D’Adda Di Fagagna, F. 2007. Cellular senescence: When bad things happen to good cells. Nature Reviews Molecular Cell Biology, 8: 729–740.

Chang, J.T., Kumsta, C., Hellman, A.B., Adams, L.M. and Hansen, M. 2017. Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging. eLife, 6: 1–23.

Dick, F.A. and Rubin, S.M. 2013. Molecular mechanisms underlying RB protein function. Nature Reviews Molecular Cell Biology, 14: 297–306.

Dimri, G.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E.E., Linskens, M., Rubelj, I., Pereira-Smith, O., Peacocke, M. and Campisi, J. 1995. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America, 92: 9363–9367.

Donati, A., Cavallini, G., Paradiso, C., Vittorini, S., Pollera, M., Gori, Z. and Bergamini, E. 2001. Age-related changes in the regulation of autophagic proteolysis in rat isolated hepatocytes. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 56: B288–B293.

Edrey, Y.H., Park, T.J., Kang, H., Biney, A. and Buffenstein, R. 2011. Endocrine function and neurobiology of the longest-living rodent, the naked mole-rat. Experimental Gerontology, 46: 116–123.

Frisch, S.M. and Screaton, R.A. 2001. Anoikis mechanisms. Current Opinion in Cell Biology, 13: 555–562.

Hansen, M., Chandra, A., Mitic, L.L., Onken, B., Driscoll, M. and Kenyon, C. 2008. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genetics, 4.

Hernandez-Segura, A., Nehme, J. and Demaria, M. 2018. Hallmarks of Cellular Senescence. Trends in Cell Biology, 28: 436–453.

Hosokawa, N., Hara, Y. and Mizushima, N. 2006. Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Letters, 580: 2623–2629.

Hwang, S.H., Han, B.I. and Lee, M. 2018. Knockout of ATG5 leads to malignant cell transformation and resistance to Src family kinase inhibitor PP2. Journal of Cellular Physiology, 233: 506–515.

Ichimura, Y., Kirisako, T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T. and Ohsumi, Y. 2000. A ubiquitin-like system mediates protein lipidation. Nature, 408: 488–492.

Iwashita, H., Sakurai, H.T., Nagahora, N., Ishiyama, M., Shioji, K., Sasamoto, K., Okuma, K., Shimizu, S. and Ueno, Y. 2018. Small fluorescent molecules for monitoring autophagic flux. FEBS Letters, 592: 559–567.

Jarvis, J.U.M. 1981. Eusociality in a mammal: Cooperative breeding in naked mole-rat colonies. Science, 212: 571–573.

Jia, K. and Levine, B. 2007. Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy, 3: 597–599.

Kaushik, S., Arias, E., Kwon, H., Lopez, N.M., Athonvarangkul, D., Sahu, S., Schwartz, G.J., Pessin, J.E. and Singh, R. 2012. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Reports, 13: 258–265.

Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T. and Mizushima, N. 2004. The role of autophagy during the early neonatal starvation period. Nature, 432: 1032–1036.

Lewis, K.N. and Buffenstein, R. 2015. The Naked Mole-Rat: A Resilient Rodent Model of Aging, Longevity, and Healthspan. A Resilient Rodent Model of Aging, Longevity, and Healthspan. Handbook of the Biology of Aging: Eighth Edition, 179–204.

Liang, S., Mele, J., Wu, Y., Buffenstein, R. and Hornsby, P.J. 2010. Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell, 9: 626–635.

Mauthe, M., Orhon, I., Rocchi, C., Zhou, X., Luhr, M., Hijlkema, K.J., Coppes, R.P., Engedal, N., Mari, M. and Reggiori, F. 2018. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy, 14: 1435–1455.

Meléndez, A., Tallóczy, Z., Seaman, M., Eskelinen, E.L., Hall, D.H. and Levine, B. 2003. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science, 301: 1387–1391.

Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabey, Y., Suzuki, K., Tokuhis, T., Ohsumi, Y. and Yoshimori, T. 2001. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. Journal of Cell Biology, 152: 657–667.

Mizushima, N., Yoshimori, T. and Levine, B. 2010. Methods in Mammalian Autophagy Research. Cell, 140: 313–326.

Morselli, E., Maiuri, M.C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S.A., Vitale, I., Michaud, M., Madeo, F., Tavernarakis, N. and Kroemer, G. 2010. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death and Disease, 1: 1–10.

Nakamura, S., Oba, M., Suzuki, M., Takahashi, A., Yamamuro, T., Fujiwara, M., Ikenaka, K., Minami, S., Tabata, N., Yamamoto, K., Kubo, S., Tokumura, A., Akamatsu, K., Miyazaki, Y., Kawabata, T., Hamasaki, M., Fukui, K., Sango, K., Watanabe, Y., et al. 2019. Suppression of autophagic activity by Rubicon is a signature of aging. Nature Communications, 10: 1–11.

Ohtani, N. 2004. The p16INK4a-RB pathway: molecular link between cellular senescense and tumor suppression. The Journal of Medical Investigation, 51: 146– 153.

Paoli, P., Giannoni, E. and Chiarugi, P. 2013. Anoikis molecular pathways and its role in cancer progression. Biochimica et Biophysica Acta - Molecular Cell Research, 1833: 3481–3498.

Pyo, J.O., Yoo, S.M., Ahn, H.H., Nah, J., Hong, S.H., Kam, T.I., Jung, S. and Jung, Y.K. 2013. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature Communications, 4: 1–9.

Rufini, A., Tucci, P., Celardo, I. and Melino, G. 2013. Senescence and aging: The critical roles of p53. Oncogene, 32: 5129–5143.

Seluanov, A., Hine, C., Azpurua, J., Feigenson, M., Bozzella, M., Mao, Z., Catania, K.C. and Gorbunova, V. 2009. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proceedings of the National Academy of Sciences of the United States of America, 106: 19352–19357.

Simonsen, A., Cumming, R.C., Brech, A., Isakson, P., Schubert, D.R. and Finley, K.D. 2008. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy, 4: 176–184.

Sullivan, K.D., Galbraith, M.D., Andrysik, Z. and Espinosa, J.M. 2018. Mechanisms of transcriptional regulation by p53. Cell Death and Differentiation, 25: 133–143.

Tal, M.C., Sasai, M., Lee, H.K., Yordy, B., Shadel, G.S. and Iwasaki, A. 2009. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proceedings of the National Academy of Sciences of the United States of America, 106: 2774–2775.

Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V. and Seluanov, A. 2013. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature, 499: 346– 349.

Tian, X., Azpurua, J., Ke, Z., Augereau, A., Zhang, Z.D., Vijg, J., Gladyshev, V.N., Gorbunova, V. and Seluanov, A. 2015. INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. Proceedings of the National Academy of Sciences of the United States of America, 112: 1053– 1058.

Ulgherait, M., Rana, A., Rera, M., Graniel, J. and Walker, D.W. 2014. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Reports, 8: 1767–1780.

White, E. 2016. Autophagy and p53. Cold spring Harbor Perspectives in Medicine, 6:a0 26120

Qiang, L., Zhao, B., Ming, M., Wang, N., He, T.C., Hwang, S., Thorburn, A. and He, Y.Y. 2014. Regulation of cell proliferation and migration by p62 through stabilization of Twist1. Proceedings of the National Academy of Sciences of the United States of America, 111: 9241–9246.

Zhao, S., Lin, L., Kan, G., Xu, Chang, Tang, Q., Yu, C., Sun, W., Cai, L., Xu, Chen and Cui, S. 2014. High autophagy in the naked mole rat may play a significant role in maintaining good health. Cellular Physiology and Biochemistry, 33: 321–332.

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