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The Atg12-Atg5 Conjugate Has a Novel E3-like Activity for Protein Lipidation in Autophagy
Open accessAbstract
Autophagy is a bulk degradation process in eukaryotic cells; autophagosomes enclose cytoplasmic components for degradation in the lysosome/vacuole. Autophagosome formation requires two ubiquitin-like conjugation systems, the Atg12 and Atg8 systems, which are tightly associated with expansion of autophagosomal membrane. Previous studies have suggested that there is a hierarchy between these systems; the Atg12 system is located upstream of the Atg8 system in the context of Atg protein organization. However, the concrete molecular relationship is unclear. Here, we show using an in vitro Atg8 conjugation system that the Atg12-Atg5 conjugate, but not unconjugated Atg12 or Atg5, strongly enhances the formation of the other conjugate, Atg8-PE. The Atg12-Atg5 conjugate promotes the transfer of Atg8 from Atg3 to the substrate, phosphatidylethanolamine (PE), by stimulating the activity of Atg3. We also show that the Atg12-Atg5 conjugate interacts with both Atg3 and PE-containing liposomes. These results indicate that the Atg12-Atg5 conjugate is a ubiquitin-protein ligase (E3)-like enzyme for Atg8-PE conjugation reaction, distinctively promoting protein-lipid conjugation.
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“Two ubiquitin-like conjugation systems also contribute to autophagosome formation [23,24,25].”
From LC3-Associated Phagocytosis (LAP): Connections with Host Autophagy (2012) · cites this paper as [25]
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BackgroundInfluentialFIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells
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“Moreover, the Atg12–Atg5 conjugate may act as an E3-like enzyme for the conjugation of Atg8s to PE and, together with Atg16, is responsible for their recruit- ment to the phagophore (Hanada et al, 2007; Fujita et al, 2008b).”
BackgroundAtg8 Controls Phagophore Expansion during Autophagosome Formation
Xie, Z., Nair, U., & Klionsky, D. J. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-12-1292 · Cited by 753
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“The exposed C-terminus of LC3 is conjugated to the head group amine of phosphatidylethanolamine (PE) by a ubiquitin-like system composed of Atg7 (E1 enzyme), Atg3 (E2 enzyme), and the Atg12–Atg5–Atg16L complex (E3 enzyme) (Ichimura et al , 2000; Hanada et al , 2007; Fujita et al , 2008b).”
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“The reaction proceeds similarly to the conjugation of ubiquitin to lysine residues in target proteins and requires Atg7 as the activating enzyme (E1), Atg3 as the conjugating enzyme (E2) and the Atg12 – Atg5 – Atg16 protein complex as the E3-like enzyme [73,75,76].”
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“This ATG5– ATG12 conjugate interacts with ATG16L, and this complex then promotes LC3 lipidation (Hanada et al. 2007; Fujita et al. 2008).”
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“Finally, Atg8 is conjugated to a phosphatidyletha-nolamine [16], in a process in which the E3-like Atg12–Atg5–Atg16 complex plays a crucial role [41–43].”
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“…to the head group amine of phosphatidylethanolamine (PE) through an amide bond by a sequence of ubiquitination-like reactions that involves an E1 (Atg7), an E2 (Atg3), and an E3 (protein complex including Atg5, Atg12, and Atg16L; Ichimura et al., 2000; Hanada et al., 2007; Fujita et al., 2008).”
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“Atg8 is upregulated at the transcriptional level (23), and it undergoes phosphatidylethanolamine conjugation (Atg8-PE) mediated by the Atg12-Atg5 complex (6).”
BackgroundSelf-citationRomanov, J., Walczak, M., Ibiricu, I., Schüchner, S., Ogris, E., Kraft, C., & Martens, S. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.278 · Cited by 499
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InfluentialThe ATG conjugation systems in autophagy
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“Recently, it has been suggested that the Atg12-Atg5 conjugate acts as an E3-like enzyme in the conjugation of Atg8 to PE and that together with Atg16 it recruits Atg8s to the phagophore membrane (Hanada et al., 2007; Fujita et al., 2008b).”
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“LC3 is a homologue of Apg8 and essential for the formation of the autophagosome,(25) whereas ATG5 and ATG12 are part of an ubiquitin-like conjugation system, which is associated with a protein/phospholipids complex that localizes to the autophagosomal membranes.(26,27) The importance of the increased expression of LC3…”
BackgroundTargeting autophagy using natural compounds for cancer prevention and therapy
Deng, S., Shanmugam, M. K., Kumar, A. P., Yap, C. T., Sethi, G., & Bishayee, A. (2019) · Cancer · doi:10.1002/cncr.31978 · Cited by 324
“ATG5-ATG12 can act as an E3 enzyme to conjugate LC3 into a membrane-bound PE group, giving rise to LC3-PE known as LC3-II (widely used autophagy markers in immunoblot analyses).(49) LC3-II located on the phagophore recruits subsequent modulators, mainly through the LC3interacting region presented on those modulators,…”
BackgroundBodemann, B. O., Orvedahl, A., Cheng, T., Ram, R. R., Ou, Y.-H., Formstecher, É., Maiti, M., Hazelett, C. C., Wauson, E., Balakireva, M., et al. (2011) · Cell · doi:10.1016/j.cell.2010.12.018 · Cited by 325
Chung, T., Phillips, A. R., & Vierstra, R. D. (2010) · The Plant Journal · doi:10.1111/j.1365-313x.2010.04166.x · Cited by 285
Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy
Nakatogawa, H. (2013) · Essays in Biochemistry · doi:10.1042/bse0550039 · Cited by 322
“Although the Atg12–Atg5 conjugate enhances the E2 activity of Atg3 (see below), it does not aff ect the substrate preference of Atg3 [15].”
BackgroundEmerging roles of ATG proteins and membrane lipids in autophagosome formation
Nishimura, T., & Tooze, S. A. (2020) · Cell Discovery · doi:10.1038/s41421-020-0161-3 · Cited by 323
Posttranslational modification of autophagy-related proteins in macroautophagy
Xie, Y., Kang, R., Sun, X., Zhong, M., Huang, J., Klionsky, D. J., & Tang, D. (2015) · Autophagy · doi:10.4161/15548627.2014.984267 · Cited by 302
MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5
Nezich, C. L., Wang, C., Fogel, A. I., & Youle, R. J. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201501002 · Cited by 309
Autophagy in Ovarian Follicular Development and Atresia
Zhou, J., Peng, X., & Mei, S. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.30369 · Cited by 317
“ATG5-ATG12 conjugates then interact non-covalently with ATG16L1 to form an E3-like complex [19].”
BackgroundSuzuki, K., Akioka, M., Kondo‐Kakuta, C., Yamamoto, H., & Ohsumi, Y. (2013) · Journal of Cell Science · doi:10.1242/jcs.122960 · Cited by 330
“Our group has reported that Atg12–Atg5 exerts an E3-like function in the conjugation of Atg8 with phosphatidylethanolamine (PE) to produce Atg8–PE (Hanada et al., 2007).”
BackgroundSelf-citationThe multiple roles of autophagy in cancer
Rosenfeldt, M. T., & Ryan, K. M. (2011) · Carcinogenesis · doi:10.1093/carcin/bgr031 · Cited by 311
The Cvt pathway as a model for selective autophagy
Lynch-Day, M. A., & Klionsky, D. J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.02.013 · Cited by 329
The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases
Wang, H., Liu, Y., Wang, D., Xu, Y., Dong, R., Yang, Y., Lv, Q., Chen, X., & Zhang, Z. (2019) · Cells · doi:10.3390/cells8121597 · Cited by 286
“Finally, the C-terminal glycine of LC3-I is covalently bound to PE (ATG12-ATG5-ATG16L1 complex may be used as E3-like ligase to facilitate this last step) [38,40].”
BackgroundDynamic regulation of macroautophagy by distinctive ubiquitin-like proteins
Klionsky, D. J., & Schulman, B. A. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2787 · Cited by 284
Phosphatidylethanolamine positively regulates autophagy and longevity
Rockenfeller, P., Koska, M., Pietrocola, F., Minois, N., Knittelfelder, O. L., Sica, V., Franz, J., Carmona‐Gutiérrez, D., Kroemer, G., & Madeo, F. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2014.219 · Cited by 278
Non‐autophagic roles of autophagy‐related proteins
Subramani, S. E., & Malhotra, V. (2013) · EMBO Reports · doi:10.1038/embor.2012.220 · Cited by 286
Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer
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“As the nascent autophagosome elongates, Atg7, Atg3, and Atg5–Atg12 function as E1, E2, and E3 ubiquitin-like conjugation proteins to covalently attach PE to microtubuleassociated protein/light chain 3 (LC3) to facilitate LC3 attachment to autophagosomal membranes (Hanada et al., 2007; Noda et al., 2011).”
BackgroundLC3-Associated Phagocytosis and Inflammation
Heckmann, B. L., Boada-Romero, E., Cunha, L. D., Magne, J., & Green, D. R. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.08.012 · Cited by 276
“Finally, LC3 is transferred from the ATG3-LC3 heterodimer to the lipid, using the E3 ligase activity of the ATG16L complex [81].”
Molecular Mechanisms of Autophagy in the Cardiovascular System
Gatica, D., Chiong, M., Lavandero, S., & Klionsky, D. J. (2015) · Circulation Research · doi:10.1161/circresaha.114.303788 · Cited by 272
Golgi-resident Small GTPase Rab33B Interacts with Atg16L and Modulates Autophagosome Formation
Itoh, T., Fujita, N., Kanno, E., Yamamoto, A., Yoshimori, T., & Fukuda, M. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-12-1231 · Cited by 283
“Our results, together with a recent report that yeast Atg12-conjugated Atg5 promotes conjugation between Atg8 and PE in vitro (Hanada et al., 2007), suggest that Rab33B promotes LC3-PE conjugation to recruit the Atg5–12/16L complex to the Rab33B-localized membrane in mammalian cells.”
ResultATG12 Conjugation to ATG3 Regulates Mitochondrial Homeostasis and Cell Death
Radoshevich, L., Murrow, L., Chen, N., Fernandez, E., Roy, S., Fung, C., & Debnath, J. (2010) · Cell · doi:10.1016/j.cell.2010.07.018 · Cited by 290
“Although ATG12 and ATG8 possess little primary sequence homology to ubiquitin, both contain an ''ubiquitin superfold'' and the C-terminal glycine required for isopeptide linkage (Hanada and Ohsumi, 2005; Sugawara et al., 2004; Suzuki et al., 2005).”
InfluentialNath, S., Dancourt, J., Shteyn, V., Puente, G., Fong, W. M., Nag, S., Bewersdorf, J., Yamamoto, A., Antonny, B., & Melia, T. J. (2014) · Nature Cell Biology · doi:10.1038/ncb2940 · Cited by 279
An overview of macroautophagy in yeast
Wen, X., & Klionsky, D. J. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.02.021 · Cited by 261
“[111] Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, et al.”
Enhancing Immunity Through Autophagy
Münz, C. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132537 · Cited by 269
“However, because of its requirement in and facilitation of Atg8 conjugation, investigators have proposed that the Atg5-Atg12/Atg16L1 complex functions as an E3-like ligase for Atg8 lipidation, catalyzing this reaction and determining the site of Atg8 attachment (20, 21).”
BackgroundThe Atg8 family: multifunctional ubiquitin-like key regulators of autophagy
Rawet-Slobodkin, M., & Elazar, Z. (2013) · Essays in Biochemistry · doi:10.1042/bse0550051 · Cited by 259
“It has been shown that the localization of the Atg12–Atg5–Atg16 complex dictates the site of Atg8 lipidation and facilitates the lipidation reaction by promoting the transfer of Atg8 from Atg3 to PE thus acting as a ubiquitin ligase (E3)-like enzyme [15].”
BackgroundAutophagy and Macrophage Functions: Inflammatory Response and Phagocytosis
Wu, M.-Y., & Lu, J. (2019) · Cells · doi:10.3390/cells9010070 · Cited by 274
Reconstitution of autophagosome nucleation defines Atg9 vesicles as seeds for membrane formation
Sawa-Makarska, J. Z., Baumann, V., Coudevylle, N., von Bülow, S., Nogellova, V., Abert, C., Schuschnig, M., Graef, M., Hummer, G., & Martens, S. (2020) · Science · doi:10.1126/science.aaz7714 · Cited by 262
“6xHis-TEV-Atg21, 6xHis-TEV-mEGFP-Atg21, 6xHis-TEV-mCherry-Atg21, 6xHis-Atg18-mEGFP, andAtg9-NTD(1-285)-mEGFPwere all expressed in E.”
BackgroundMethodInfluentialCaspases: A Molecular Switch Node in the Crosstalk between Autophagy and Apoptosis
Wu, H., Che, X., Zheng, Q., Wu, A., Pan, K., Shao, A., Wu, Q., Zhang, J., & Hong, Y. (2014) · International Journal of Biological Sciences · doi:10.7150/ijbs.9719 · Cited by 259
“This complex serves as a platform for stimulating the LC3-PE conjugation reaction [42, 43], which is essential for the elongation of the pre-autophagosomal membranes [44, 45].”
BackgroundDual roles of Atg8−PE deconjugation by Atg4 in autophagy
Yu, Z.-Q., Ni, T., Hong, B., Wang, H.-Y., Jiang, F.-J., Zou, S., Chen, Y., Zheng, X., Klionsky, D. J., Liang, Y., et al. (2012) · Autophagy · doi:10.4161/auto.19652 · Cited by 258
Molecular Mechanism of Autophagic Membrane-Scaffold Assembly and Disassembly
Kaufmann, A., Beier, V., Franquelim, H. G., & Wollert, T. (2014) · Cell · doi:10.1016/j.cell.2013.12.022 · Cited by 242
Autophagy, lipophagy and lysosomal lipid storage disorders
Ward, C., Martínez-López, N., Otten, E. G., Carroll, B., Maetzel, D., Singh, R., Sarkar, S., & Korolchuk, V. I. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.01.006 · Cited by 254
“Furthermore, autophagosome and lysosome fractions from fasted mice both contained LD-associated PLINs, and liver-isolated LDs co-purified with autophagosome marker LC3-II [80].”
BackgroundInfluentialA role for Atg8–PE deconjugation in autophagosome biogenesis
Nair, U., Yen, W.-L., Mari, M. C., Cao, Y., Xie, Z., Baba, M., Reggiori, F., & Klionsky, D. J. (2012) · Autophagy · doi:10.4161/auto.19385 · Cited by 249
Metadata
- Authors
- Hanada, T., Noda, N. N., Satomi, Y., Ichimura, Y., Fujioka, Y., Takao, T., Inagaki, F., & Ohsumi, Y.
- Affiliations
- National Institute for Basic Biology (JP)
- Hokkaido University (JP)
- Institute for Protein Research, The University of Osaka (JP)
- Corresponding author
- Ohsumi, Yoshinori
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 282
- Issue
- 52
- Pages
- 37298-37302
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2040157483
- Semantic Scholar
- ac42037b48b9d80a5e5c15efd2379440ed23b91c
- Cited by
- 1,123
- References
- 28
- Citations by year
- 2026: 31 · 2025: 38 · 2024: 44 · 2023: 55 · 2022: 59 · 2021: 68 · 2020: 75 · 2019: 87 · 2018: 61 · 2017: 54 · 2016: 79 · 2015: 77 · 2014: 64 · 2013: 65 · 2012: 81
- FWCI
- 28.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Tokyo Tech Research Repository (Tokyo Institute of Technology) (submittedVersion)
- 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
- ATG12-ATG5 conjugate, protein lipidation, E3 ubiquitin ligase activity, autophagy, ATG3, ATG12, ATG8, phosphatidylethanolamine, autophagosome formation, liposome binding
- MeSH terms
- Autophagy-Related Protein 5, Autophagy-Related Protein 12, Autophagy, Escherichia coli, Lipids, Liposomes, Models, Biological, Protein Processing, Post-Translational, Saccharomyces cerevisiae, Time Factors, Gene Expression Regulation, Fungal, Ubiquitin, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases
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