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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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“The phagophore is produced by polymerization of Atg8 (LC3) and Atg12-Atg5 UBL conjugation systems (Kihara et al., 2001; Ohsumi, 2001).”
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“ATG8–PE modified autophagosomes ultimately become mature and form closed double-membrane structures, with the help of tubulins and other proteins, then fused into the vacuoles or lysosomes, and eventually degraded (Ohsumi, 2001a; Li & Vierstra, 2012; Lv et al., 2014).”
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“It has two very critical roles in eukaryotic cells [18,19]: one is nutrient recycling, and the second is eliminating excessive or harmful cellular products such as protein aggregates, supramolecular structures, or organelles such as mitochondria or peroxisomes.”
BackgroundThe interaction of ER stress and autophagy in trophoblasts: navigating pregnancy outcome
Zheng, Y., Zha, X., Zhang, B., Elsabagh, M., Wang, H., Wang, M., & Zhang, H. (2024) · Biology of Reproduction · doi:10.1093/biolre/ioae066 · Cited by 19
Clathrin light chains negatively regulate plant immunity by hijacking the autophagy pathway
Lan, H.-J., Ran, J., Wang, W., Zhang, L., Wu, N.-N., Zhao, Y., Huang, M., Ni, M., Liu, F., Cheng, N., et al. (2024) · Plant Communications · doi:10.1016/j.xplc.2024.100937 · Cited by 15
“The lipid molecule phosphatidylethanolamine (PE) is then conjugated to the exposed Gly residue of ATG8 with the sequential assistance of the E1-like enzyme ATG7 and the E2-like enzyme ATG3 (Ohsumi, 2001; Seo et al., 2016).”
Niazpour, F., & Meshkani, R. (2025) · Phytotherapy Research · doi:10.1002/ptr.8463 · Cited by 16
“Several enzymatic reactions participate in the process of converting LC3-I into LC3-II, which is associated with phagophore expansion (Ohsumi 2001).”
Salto, R., Vílchez, J. D., Cabrera, E., Guinovart, J. J., & Girón, M. D. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.05.004 · Cited by 16
“The role of the lysosomal system, also called autophagy, in the atrophic effect of GCs is proposed to occur via the increased conversion of LC3-I to LC3-II, the latter an indicator of autophagy [8,9,11,23].”
BackgroundInfluentialAutophagy: From basic research to its application in food biotechnology
Cebollero, E., & Gonzalez, R. (2007) · Biotechnology Advances · doi:10.1016/j.biotechadv.2007.03.004 · Cited by 16
Song, H., Du, C., Wang, X., Zhang, J., & Shen, Z. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4077 · Cited by 16
“The latter then fuse with lysosomes to form autolysosomes, and the intra-vesicular contents are degraded by the lysosomal enzymes (29).”
BackgroundAn Overview of the Molecular Mechanisms and Functions of Autophagic Pathways in Plants
Yang, Y., Xiang, Y., & Niu, Y. (2021) · Plant Signaling & Behavior · doi:10.1080/15592324.2021.1977527 · Cited by 18
“Subsequently, starvation-induced ATG8 is modified with PE and then conjugated to the autophagosome precursor (phagophore).(60) In the Arabidopsis genome, there are two homologs of the ATG4 gene, termed ATG4a and ATG4b.”
BackgroundSasaki, M., Kakuda, Y., Miyakoshi, M., Sato, Y., & Nakanuma, Y. (2014) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2013-201917 · Cited by 16
Autophagy as an antimicrobial strategy
Subauste, C. S. (2009) · Expert Review of Anti-infective Therapy · doi:10.1586/eri.09.41 · Cited by 18
“27 Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG gene is essential for autophagosome formation. EMBO J. 20, 5971–5981 (2001).”
BackgroundRescue of CFTR NBD2 mutants N1303K and S1235R is influenced by the functioning of the autophagosome
Liu, Q., Sabirzhanova, I. B., Yanda, M. K., Bergbower, E. A. S., Boinot, C., Guggino, W. B., & Cebotaru, L. (2018) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2018.05.016 · Cited by 16
“These are processed by the phagophor to from autophagosomes, double-membrane structures that ultimately latter fuse with lysosomes to degrade the misfolded proteins [23].”
The Role of Alternative Mitophagy in Heart Disease
Nah, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076362 · Cited by 16
“Two ubiquitin-like systems, Atg12 and Atg8/LC3 conjugation, essentially act as E3-like systems in LC3-PE (LC3-II) conjugation [15].”
BackgroundAutophagy facilitates cytokine-induced ICAM-1 expression
Wang, C., Chiang, T.-H., Chen, C., Tseng, P., Chien, S.-Y., Chuang, Y.-J., Yang, T.-T., Hsieh, C.-Y., Choi, P.-C., & Lin, C. (2013) · Innate Immunity · doi:10.1177/1753425913488227 · Cited by 15
Stress-induced cellular responses and cell death mechanisms during inflammatory cholangiopathies
Sasaki, M., & Nakanuma, Y. (2016) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2016.08.002 · Cited by 15
Yamazaki-Sato, H., Tanida, I., Ueno, T., & Kominami, E. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00899-8 · Cited by 15
Biliary Epithelial Apoptosis, Autophagy, and Senescence in Primary Biliary Cirrhosis
Sasaki, M., & Nakanuma, Y. (2010) · Hepatitis Research and Treatment · doi:10.1155/2010/205128 · Cited by 16
“This evolutionarily conserved process is characterized by the formation of double-membrane cytosolic vesicles, autophagosomes, which sequester the cytoplasmic content and deliver it to lysosomes [71, 72].”
BackgroundRole of adiponectin in osteoarthritis
Feng, X., Xiao, J., & Bai, L. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.992764 · Cited by 15
“Two other protein conjugation systems, ATG–microtubule-associated protein light chain 3 (LC3) and the ATG5–ATG12 conjugation system, typically used as autophagy biomarkers, play a role in the elongation of the autophagosome membrane (Ohsumi, 2001).”
BackgroundFluoride-Induced Mitochondrial Dysfunction and Approaches for Its Intervention
Kumar, S., Shenoy, S., Swamy, R. S., Ravichandiran, V., & Kumar, N. (2023) · Biological Trace Element Research · doi:10.1007/s12011-023-03720-1 · Cited by 14
“Macroautophagy, or autophagy as it is more widely known, is an intracellular catabolic process that is phylogenetically conserved and allows the breakdown of cytoplasmic content [66–68], such as defective proteins and organelles.”
Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches
Rashid, S., & Dimitriadi, M. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1307636 · Cited by 17
“…into the membrane, LC3 undergoes proteolytic processing by ATG4 into LC3-I, subsequently bound by ATG7 and ATG3 and lastly, conjugated by phosphatidylethanolamine (PE) - the resulting mature form of LC3 is referred to as LC3-II (Kirisako et al., 2000; Ohsumi, 2001; Mizushima et al., 2011).”
BackgroundFundamental mechanisms of cell death for polycystic ovary syndrome
Li, Y., Peng, Y., Yang, Y., Xu, N., Shi, T., Liu, R., Luan, Y., & Yin, C.-H. (2025) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2025.102043 · Cited by 14
“It is particularly worth mentioning that LC3-II is like a “ molecular tag ” of the autophagosome, which not only promotes the extension of the membrane structure, but also selectively identifies the substances to be degraded through receptor proteins such as P62 [55 – 57].”
Autophagy facilitates an IFN-γ response and signal transduction
Chang, Y.-P., Chen, C., Chen, S.-O., Lin, Y.-S., Tsai, C., Huang, W., Wang, C., Hsieh, C.-Y., Choi, P.-C., & Lin, C. (2011) · Microbes and Infection · doi:10.1016/j.micinf.2011.05.008 · Cited by 18
“Two protein conjugation systems have been shown to be necessary for autophagosome formation including the Atg12Atg5 and Atg8-phosphatidylethanolamine (PE) conjugation systems, which share a single E1-like activating enzyme, Atg7 [45].”
Background
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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