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Molecular dissection of autophagy: two ubiquitin-like systems
Abstract
Recent analyses of the genes required for autophagy--intracellular bulk protein degradation--in yeast have revealed two ubiquitin-like systems, both of which are involved in the membrane dynamics of the process. Molecular dissection of these systems is now revealing some surprises.
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“One universal activator of autophagy is a decrease in nutrient availability and this stimulation occurs, at least in part, by the inhibition of TOR (target of rapamycin) signalling 74 .”
From The common biology of cancer and ageing (2007) · cites this paper as [74]
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“However, Atg8 has been widely used as a specific marker of autophagosomes (Ohsumi 2001) because the lipidated Atg8 form (Atg8-PE) is localized in autophagosome membranes (Kabeya et al. 2000).”
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“…of autophagy is a PCD which resembles with apoptosis and entirely dependent on protein synthesis as well as continuous ATP production as it is an energy dependent process (Schwartzman and Cidlowski, 1993; Ohsumi, 2001; Huang and Klionsky, 2002; Gozuacik and Kimchi, 2004; Debnath et al., 2005).”
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“Among those genes, a suite of members is involved in autophagosome formation, including the ATG8/ATG12 ubiquitin-like conjugation system (Ohsumi 2001; Yoshinori 2014).”
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“…is proteolytically processed to a shorter form (referred to as LC3-I) which is then conjugated to the membrane bound lipid phosphatidylethanolamine; the lipid modi fi ed form of LC3 (referred to as LC3-II), along with SQSTM1 and other cargo proteins, is fi nally degraded in the autolysome (28, 29).”
Loss of NDR1/2 kinases impairs endomembrane trafficking and autophagy leading to neurodegeneration
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“Macroautophagy (hereafter referred to as autophagy) is a degradation process for cytoplasmic organelles and proteins (Ohsumi, 2001; Yorimitsu & Klionsky, 2005; Klionsky et al, 2010; Mizushima & Komatsu, 2011; Yamamoto& Yue, 2014; Yu et al, 2018).”
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“The ATG5-ATG12-ATG16L1 complex plays a crucial role in elongating autophagic vacuoles and acts as a platform for ATG8 lipidation (Ohsumi, 2001; Fujita et al., 2008; Fahmy and Labonté, 2017).”
BackgroundGu, M., Liu, Y., Xin, P., Guo, W., Zhao, Z., Xu, Y., Ma, R., Jiao, T., & Zheng, W. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216738 · Cited by 13
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Autophagy—an underestimated coordinator of construction and destruction during plant root ontogeny
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“ATG8 genes encode ubiquitin-like proteins, which are required for the formation of autophagosomes and are responsible for their size regulation (Ohsumi 2001; Xie et al. 2008).”
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“times of nutrient deprivation and to remove damaged cell components [59,60].”
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Dwivedi, M., & Ahnn, J. (2009) · BMB Reports · doi:10.5483/bmbrep.2009.42.2.065 · Cited by 14
“Expansion and completion of the autophagosome Two sets of conjugation complexes involving ubiqutin-like (Ubl) proteins participate in the expansion and completion of autophagosomes (19, 33, 34), the Atg12 system and the Atg8”
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“134 The second system is the microtubule-associated protein 1 light chain 3 LC3 conjugate (LC3 is one of the mammalian homologues of ATG8).”
Cao, Y., He, X., Liu, Z., Miao, L., & Zhu, B. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e41501 · Cited by 12
The ULK1 kinase, a necessary component of the pro-regenerative and anti-aging machinery in Hydra
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“The molecular actors of the autophagy process were initially identified in yeast mutants that could not survive long-term starvation (Ohsumi, 2001; Matecic et al., 2010).”
Relish regulates innate immunity via mediating ATG5 activity in Antheraea pernyi
Chen, C., Yang, L., Abbas, M. N., Zou, D., Li, J., Geng, X., Zhang, H., & Sun, Y. (2022) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2022.104406 · Cited by 12
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“cerevisiae, Atg4 interacts directly with Atg8 by cleaving its carboxyl-terminal end, and this truncated Atg8 is indispensable for the conjugation of Atg8-PE [21,39].”
BackgroundAtg5 regulates formation of MyD88 condensed structures and MyD88-dependent signal transduction
Inomata, M., Into, T., Niida, S., & Murakami, Y. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.06.094 · Cited by 13
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Münz, C. (2011) · Frontiers in Microbiology · doi:10.3389/fmicb.2011.00072 · Cited by 13
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BackgroundInfluentialNutrient starvation differentially regulates the autophagy-related gene GmATG8i in soybean seedlings
Htwe, N. M. P. S., Tanigawa, H., Ishibashi, Y., Zheng, S.-H., Yuasa, T., & Iwaya‐Inoue, M. (2009) · Plant Biotechnology · doi:10.5511/plantbiotechnology.26.317 · Cited by 12
“It was reported that combination of sucrose starvation and protease inhibitors generates autophagosomes in vacuoles of Arabidopsis and yeast (Ohsumi 2001; Rose et al. 2006).”
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Liu, N., Ning, G., Liu, X., Feng, X., Lu, J., Mao, L., Su, Z.-Z., Wang, Y., Zhang, C., & Lin, F. (2016) · Microbiological Research · doi:10.1016/j.micres.2016.08.008 · Cited by 12
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Seay, M., Dinesh-Kumar, S. P., & Levine, B. (2005) · Springer eBooks · doi:10.1007/1-4020-3242-0_11 · Cited by 10
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“During macroautophagy, elongation of the isolation membrane requires the E1-like activating enzyme Atg7 and E2-like conjugating enzyme Atg10 to bring Atg12 to Atg5 (an E3-like ligase) which then binds Atg16 to form the Atg12Atg5-Atg16 multimeric complex (Ohsumi, 2001; Kuma et al., 2002).”
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BackgroundAutophagy and Autophagic Cell Death
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“However, only 20 ATG proteins belong to the core autophagic machinery used in every autophagic process, while the remaining ones are specific for certain processes, including selective autophagy (160–162).”
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Antigen processing for MHC presentation by autophagy
Münz, C. (2010) · F1000 Biology Reports · doi:10.3410/b2-61 · Cited by 9
“Two ubiquitin-like systems with the Atg8 and Atg12 proteins at their heart are involved in extension of the autophagosomal membrane and substrate recruitment to its interior [16-18].”
BackgroundZhang, M., Li, L., Wu, L., & Zhang, J. (2022) · Journal of Natural Products · doi:10.1021/acs.jnatprod.1c01161 · Cited by 8
JunB condensation attenuates vascular endothelial damage under hyperglycemic condition
Ren, X., Cui, Z., Zhang, Q., Su, Z., Xu, W., Wu, J., & Jiang, H. (2023) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjad072 · Cited by 7
Analysis of Autophagic Activity Using ATG8 Lipidation Assay in Arabidopsis thaliana
Luo, M., & Zhuang, X. (2018) · BIO-PROTOCOL · doi:10.21769/bioprotoc.2880 · Cited by 8
“Upon autophagic induction, the ATG5-ATG12 conjugate forms and functions as an E3-like enzyme to promote ATG8 lipidation for binding to the phosphatidylethanolamine (PE) on the autophagosome membrane (Ohsumi, 2001).”
BackgroundLiu, T., Ling, C., Tian, J., & Ma, F. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.04.081 · Cited by 8
A novel ATG5 interaction with Ku70 potentiates DNA repair upon genotoxic stress
Demirbag-Sarikaya, S., Akkoç, Y., Turgut, S., Erbil-Bilir, S., Kocatürk, N. M., Dengjel, J., & Gözüaçık, D. (2022) · Scientific Reports · doi:10.1038/s41598-022-11704-9 · Cited by 8
In Vitro Assays of Lipidation of Mammalian Atg8 Homologs
Tanida, I., Ueno, T., & Kominami, E. (2014) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb1120s64 · Cited by 8
“…& Sons, Inc. Keywords: ubiquitin-like modifier autophagy UBL Atg8 GABARAP GATE-16 LC3 INTRODUCTION Ubiquitylation and ubiquitylation-like post-translational reactions play indispensable roles in many cellular functions (Ohsumi, 2001; Glickman and Ciechanover, 2002; Schwartz and Hochstrasser, 2003).”
BackgroundGu, X., Yan, L., Chen, J., He, H., Li, P., Yang, T., Li, L., Liu, G., Chen, Y., & Zhang, L. (2012) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2012.05694.x · Cited by 8
“Autophagy is initiated by the induction of several proteins, such as LC3 and beclin-1.(33) Lipopolysaccharide-induced”
BackgroundTashiro, E., & Imoto, M. (2016) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2016.04.014 · Cited by 8
González‐Polo, R. A., Pizarro‐Estrella, E., Yakhine-Diop, S. M. S., Rodríguez‐Arribas, M., Gómez‐Sánchez, R., Naranjo, I. C., Pedro, J. M. B., & Fuentes, J. M. (2016) · Springer eBooks · doi:10.1007/978-3-319-30079-5_1 · Cited by 8
Low‐dose rapamycin‐induced autophagy in cochlear outer sulcus cells
Saegusa, C., Hosoya, M., Nishiyama, T., Saeki, T., Fujimoto, C., Okano, H., Fujioka, M., & Ogawa, K. (2020) · Laryngoscope Investigative Otolaryngology · doi:10.1002/lio2.392 · Cited by 8
Sass, M. (2008) · Autophagy · doi:10.4161/auto.5787 · Cited by 8
Quality Control: Proteins and Organelles
Luzikov, V. N. (2002) · Biochemistry (Moscow) · doi:10.1023/a:1014457813037 · Cited by 8
Navigating therapeutic prospects by modulating autophagy in colorectal cancer
Rajendran, D., & Oon, C. E. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.123121 · Cited by 8
ATG16L1 membrane recruitment in autophagy
Wei, F., Qin, N., Chen, Y., Liu, Z., Zhao, X., Yu, X., Feng, Z., Wang, Y., Yang, A., & Cui, H. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2521321 · Cited by 7
“…and tooze 2020). two ubiquitin-like conjugation systems are central to phagophore expansion and completion: the AtG12–AtG5 conjugation system and the microtubule-associated protein light chain 3–phosphatidylethanolamine (lc3–Pe) conjugation system (ohsumi 2001; Zhang et al. 2022; Ye et al. 2024).”
Ji, M.-M., Lee, J. M., Mon, H., Iiyama, K., Tatsuke, T., Morokuma, D., Hino, M., Yamashita, M., Hirata, K., & Kusakabe, T. (2017) · Insect Biochemistry and Molecular Biology · doi:10.1016/j.ibmb.2017.08.006 · Cited by 7
Costa, A., Erustes, A. G., Sinigaglia‐Coimbra, R., Girardi, C. E. N., Pereira, G. J. S., Ureshino, R. P., & Smaili, S. S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020135 · Cited by 8
“The macroautophagy herein referred to as autophagy involves the formation of autophagosomes with a double-membrane structure, which fuses with lysosomes to form the autophagolysosomes where the cargo is degraded and recycled [11,13,14].”
BackgroundGao, W., Kang, J. H., Liao, Y., Li, M., & Yin, X. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-381-7_30 · Cited by 7
Role of autophagy in the pathogenesis of liver diseases
Werling, K. (2011) · Orvosi Hetilap · doi:10.1556/oh.2011.29269 · Cited by 7
Crystallization and preliminary X-ray analysis of Atg10
Yamaguti, M., Suzuki, N. N., Fujioka, Y., Ohsumi, Y., & Inagaki, F. (2007) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309107017472 · Cited by 7
Self-citationCrystallization and preliminary X-ray analysis of Atg3
Yamada, Y., Suzuki, N. N., Fujioka, Y., Ichimura, Y., Ohsumi, Y., & Inagaki, F. (2006) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309106036098 · Cited by 7
Self-citationThe Role of Autophagy in Early Mammalian Embryonic Development
Tsukamoto, S., & Yamamoto, A. (2013) · Journal of Mammalian Ova Research · doi:10.1274/jmor.30.86 · Cited by 7
TEEG Induced A549 Cell Autophagy by Regulating the PI3K/AKT/mTOR Signaling Pathway
Shi, L., Tu, Y., Xia, Y., Ye, S., Ma, C., Liu, Y., & You, P. (2019) · Analytical Cellular Pathology · doi:10.1155/2019/7697610 · Cited by 7
“(LC3-II), which is used as a marker of autophagy [16, 17].”
BackgroundZhang, X., Hong, H., Yan, J., Yuan, Y., Feng, M., Liu, Q., Zhao, Y., Yang, T., Huang, S., Wang, C., et al. (2024) · Molecular Plant Pathology · doi:10.1111/mpp.70012 · Cited by 6
“During autophagy, double membrane-bound autophagosome vesicles are formed to enclose and transport cytoplasmic content to the lysosome/vacuole for degradation and recycling (Mizushima et al., 2008 ; Ohsumi, 2001; Qi et al., 2021 ).”
BackgroundProtein Prenylation in Plants: Mechanisms and Functional Implications
Tian, C., & Wang, Q. (2025) · Plants · doi:10.3390/plants14121759 · Cited by 6
“Although the specific functions of MUBs remain largely undefined [3], ubiquitin-fold proteins are known to play significant roles in various cellular processes such as protein degradation [94], SCF complex activation [95], and autophagy [96].”
Cursaro, I., Rossi, S., Butini, S., Gemma, S., Carullo, G., & Campiani, G. (2025) · Medicinal Research Reviews · doi:10.1002/med.70003 · Cited by 6
“Some of these ATG proteins are related to the UPS, playing crucial roles in the degradation pathway, yet with different roles [22].”
Metadata
- Authors
- Ohsumi, Y.
- Affiliations
- National Institute for Basic Biology (JP)
- Corresponding author
- Ohsumi, Yoshinori
- ORCID
- Ohsumi, Yoshinori
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2001-03
- Volume
- 2
- Issue
- 3
- Pages
- 211-216
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- OpenAlex
- W2792139654
- Cited by
- 1,240
- References
- 45
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 30 · 2023: 44 · 2022: 39 · 2021: 34 · 2020: 64 · 2019: 65 · 2018: 51 · 2017: 54 · 2016: 59 · 2015: 44 · 2014: 58 · 2013: 56 · 2012: 67
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- autophagy, ubiquitin-like proteins, membrane dynamics, yeast, autophagy-related genes
- MeSH terms
- Autophagy-Related Protein 8 Family, Autophagy-Related Protein 7, Autophagy, Lysosomes, Microscopy, Electron, Microtubule-Associated Proteins, Models, Biological, Proteins, Saccharomyces cerevisiae, Ubiquitins, Vacuoles, Saccharomyces cerevisiae Proteins
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