Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Biological Roles of Alternative Autophagy

  • Shimizu, Shigeomi (Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University)
  • Received : 2017.09.13
  • Accepted : 2018.01.08
  • Published : 2018.01.31
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Abstract

Atg5 and Atg7 have long been considered as essential molecules for autophagy. However, we found that cells lacking these molecules still form autophagic vacuoles and perform autophagic protein degradation when subjected to certain stressors. During this unconventional autophagy pathway, autophagosomes appeared to be generated in a Rab9-dependent manner by the fusion of vesicles derived from the trans-Golgi and late endosomes. Therefore, mammalian autophagy can occur via at least two different pathways; the Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.

Keywords

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Fig. 1. Hypothetical model of autophagy. There are atleast two modes of macroautophagy, i.e. conven-tional and alternative autophagy. Conventional au-tophagy requires Atg5 and Atg7, is associated withLC3 modification, and is thought to originate fromthe ER membrane. In contrast, alternative autophagyoccurs independently of Atg5 and Atg7, as well asLC3 modification. The generation of autophagicvacuoles in alternative autophagy is mediated by thefusion of isolation membranes with vesicles derivedfrom the trans-Golgi as well as late endosomes, in aRab9-dependent manner.

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Fig. 2. Involvement of alternative autophagy in mitochondrialclearance during erythrocyte maturation. (A) The final stage ofred blood cell maturation. During erythrocyte maturation, eryth-roblasts lose their nuclei to become reticulocytes, and reticulo-cytes transform into erythrocytes by the elimination of their mi-tochondria. Autophagy is involved in the latter process. (B)Mechanism of mitochondrial elimination during erythrocytematuration. Mitochondrial elimination mainly occurs via Ulk1-dependent alternative autophagy and only partially via Atg5-dependent conventional autophagy.

Table 1. Classification of autophagy from the view of inducers and substrates

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Table 2. Comparison between conventional and alternative au-tophagy

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References

  1. Egan, D.F., Shackelford, D.B., Mihaylova, M.M., Gelino, S., Kohnz, R.A., Mair, W., Vasquez, D.S., Joshi, A., Gwinn, D.M., Taylor, R., et al. (2011). Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456-461. https://doi.org/10.1126/science.1196371
  2. Goginashvili, A., Zhang, Z., Erbs, E., Spiegelhalter, C., Kessler, P., Mihlan, M., Pasquier, A., Krupina, K., Schieber, N., Cinque, L., et al. (2015). Insulin granules. Insulin secretory granules control autophagy in pancreatic ${\beta}$ cells. Science 347, 878-882. https://doi.org/10.1126/science.aaa2628
  3. Honda, S., Arakawa, S., Nishida, Y., Yamaguchi, H., Ishii, E., and Shimizu, S. (2014). Ulk1-mediated Atg5-independent macroautophagy mediates elimination of mitochondria from embryonic reticulocytes. Nat. Commun. 5, 4004.
  4. Itakura, E., Kishi-Itakura, C., and Mizushima, N. (2012). The hairpintype tail-anchored SNARE Syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151, 1256-1269. https://doi.org/10.1016/j.cell.2012.11.001
  5. Kaushik, S., and Cuervo, A.M. (2012). Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407-417. https://doi.org/10.1016/j.tcb.2012.05.006
  6. Kim, J., Kundu, M., Viollet, B., and Guan, K.L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132-141. https://doi.org/10.1038/ncb2152
  7. Komatsu, M., and Ichimura, Y. (2010). Selective autophagy regulates various cellular functions. Genes Cells 15, 923-933. https://doi.org/10.1111/j.1365-2443.2010.01433.x
  8. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., Kominami, E., Tanaka, K., and Chiba, T. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425-434. https://doi.org/10.1083/jcb.200412022
  9. Kundu, M., Lindsten, T., Yang, C.Y., Wu, J., Zhao, F., Zhang, J., Selak, M.A., Ney, P.A., and Thompson, C.B. (2008). Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112, 1493-1502. https://doi.org/10.1182/blood-2008-02-137398
  10. Li, W.W., Li, J., and Bao, J.K. (2012). Microautophagy: lesser-known self-eating. Cell Mol. Life Sci. 69, 1125-1136. https://doi.org/10.1007/s00018-011-0865-5
  11. Ma, T., Li, J., Xu, Y., Yu, C., Xu, T., Wang, H., Liu, K., Cao, N., Nie, B.M., Zhu, S.Y., et al. (2015). Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming. Nat. Cell Biol. 17, 1379-1387. https://doi.org/10.1038/ncb3256
  12. Mizushima, N., and Levine, B. (2010). Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12, 823-830. https://doi.org/10.1038/ncb0910-823
  13. Mizushima, N., Ohsumi, Y., and Yoshimori, T. (2002). Autophagosome Formation in Mammalian Cells Tracing of autophagosome formation with mammalian Apg proteins Initial step of autophagosome formation. Cell 429, 421-429.
  14. Nakatogawa, H., Suzuki K., Kamada, Y., and Ohsumi, Y. (2009). Dynamics and diversity in autophagy mechanisms : lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 1-10.
  15. Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T., Komatsu, M., Otsu, K., Tsujimoto, Y., and Shimizu, S. (2009). Discovery of Atg5 / Atg7-independent alternative macroautophagy. Nature 461, 654-658. https://doi.org/10.1038/nature08455
  16. Orci, L., Ravazzola, M., Amherdt, M., Yanaihara, C., Yanaihara, N., Halban, P., Renold, A.E., and Perrelet, A. (1984). Insulin, not Cpeptide (proinsulin), is present in crinophagic bodies of the pancreatic B-cell. J. Cell Biol. 98, 222-228. https://doi.org/10.1083/jcb.98.1.222
  17. Ra, E.A., Lee, T.A., Kim, S.W., Park, A, Choi, H.J., Jang, I., Kang, S., Cheon, J.H., Cho, J.W., Lee, J.E., et al. (2016). TRIM31 promotes Atg5/Atg7-independent autophagy in intestinal cells. Nature Commun. 7, Article number: 11726
  18. Shang, L., Chen, S., Du, F., Li, S., Zhao, L., and Wang, X. (2011). Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc. Natl. Acad. Sci. USA 108, 4788-4793. https://doi.org/10.1073/pnas.1100844108
  19. Tooze, S.A., and Yoshimori, T. (2010). The origin of the autophagosomal membrane. Nat. Cell Biol. 12, 831-835. https://doi.org/10.1038/ncb0910-831
  20. Torii, S., Yoshida, T., Arakawa, S., Honda, S., Nakanishi, A., and Shimizu, S. (2016). Identification of protein phosphatase 1D magnesium-dependent delta isoform as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy. EMBO R. 11, 1552-1564.
  21. Wong, P.M., Puente, C., Ganley, I.G., and Jiang, X. (2013). The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 9, 124-137. https://doi.org/10.4161/auto.23323
  22. Wong, P.M., Feng, Y., Wang, J., Shi, R. and Jiang, X. (2015). Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A. Nat. Commun 6, 8048 https://doi.org/10.1038/ncomms9048
  23. Yamaguchi, H., Arakawa, S., Kanaseki, T., Miyatsuka, T., Fujitani, Y., Watada, H., Tsujimoto, H., and Shimizu, S. (2016). Golgi membraneassociated degradation pathway in yeast and mammals. EMBO J. 35, 1991-2007. https://doi.org/10.15252/embj.201593191

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