The Atg12-Atg5 Conjugate Has a Novel E3-like Activity for Protein Lipidation in Autophagy
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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 contribute to autophagosome formation.
“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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“In this manner, we speculate that Alfy brings a membrane source and Atg5-Atg12-Atg16L to the inclusion so that they can act as part of a greater E3 ligase-like complex for LC3 (Hanada et al., 2007).”
Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy
Otomo, C., Metlagel, Z., Takaesu, G., & Otomo, T. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2431 · Cited by 432 · see citing works
Autophagic Processes in Yeast: Mechanism, Machinery and Regulation
Reggiori, F., & Klionsky, D. J. (2013) · Genetics · doi:10.1534/genetics.112.149013 · Cited by 404 · see citing works
“This complex is proposed to function as an E3like enzyme for Atg8 conjugation (Hanada et al. 2007; Noda et al. 2013; Otomo et al. 2013), but Atg8—PE can be generated in the absence of these proteins (Cao et al. 2008).”
BackgroundAutophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome
Cho, M.-H., Cho, K., Kang, H.-J., Jeon, E.-Y., Kim, H.-S., Kwon, H.-J., Kim, H.-M., Kim, D.-H., & Yoon, S.-Y. (2014) · Autophagy · doi:10.4161/auto.29647 · Cited by 395 · see citing works
Harris, J. (2011) · Cytokine · doi:10.1016/j.cyto.2011.08.022 · Cited by 392 · see citing works
“Unconjugated LC3 (LC3 I) is found in the cytosol, while PE lipidates LC3 at the C-terminus, which then translocates to the autophagosomal membrane [7,8].”
Autophagy as a molecular target for cancer treatment
Kocatürk, N. M., Akkoç, Y., Kığ, C., Bayraktar, O., Gözüaçık, D., & Kutlu, Ö. (2019) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2019.04.011 · Cited by 388 · see citing works
Mortensen, M., Ferguson, D. J. P., Edelmann, M. J., Kessler, B. M., Morten, K., Komatsu, M., & Simon, A. K. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913170107 · Cited by 388 · see citing works
“As theAtg12/ Atg5 conjugate was recently reported to have an E3-like activity enhancing Atg8 lipidation in yeast (32), it can therefore be speculated that its up-regulation in the absence of Atg7might be a way to attempt autophagosome formation and may result in an increase in the formation of isolation membranes accu…”
BackgroundAutophagy: a multifaceted intracellular system for bulk and selective recycling
Li, F., & Vierstra, R. D. (2012) · Trends in Plant Science · doi:10.1016/j.tplants.2012.05.006 · Cited by 382 · see citing works
Sarkar, S. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130134 · Cited by 367 · see citing works
Autophagy in the renewal, differentiation and homeostasis of immune cells
Clarke, A. J., & Simon, A. K. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-018-0095-2 · Cited by 361 · see citing works
A current perspective of autophagosome biogenesis
Shibutani, S., & Yoshimori, T. (2013) · Cell Research · doi:10.1038/cr.2013.159 · Cited by 361 · see citing works
van der Veen, A. G., & Ploegh, H. L. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-093010-153308 · Cited by 364 · see citing works
Noda, N. N., & Inagaki, F. (2015) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-060414-034248 · Cited by 358 · see citing works
Self-citationAutophagy and the ubiquitin-proteasome system: Collaborators in neuroprotection
Nedelsky, N. B., Todd, P. K., & Taylor, J. P. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.10.002 · Cited by 351 · see citing works
“the Atg conjugation cascade to promote lipidation of Atg8 [16].”
BackgroundInfluentialLinking ER Stress to Autophagy: Potential Implications for Cancer Therapy
Verfaillie, T., Salazar‐Roa, M., Velasco, G., & Agostinis, P. (2010) · International Journal of Cell Biology · doi:10.1155/2010/930509 · Cited by 344 · see citing works
“The last step in Atg8/LC3 modification involves the conjugation of this protein to phosphatidylethanolamine (PE), a process that is facilitated by the E3-like activity of the Atg12-Atg5 conjugate [105, 106].”
BackgroundThe independence of and associations among apoptosis, autophagy, and necrosis
Chen, Q., Kang, J., & Fu, C. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0018-5 · Cited by 348 · see citing works
Autophagy and Lipid Droplets in the Liver
Martínez-López, N., & Singh, R. (2015) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071813-105336 · Cited by 339 · see citing works
Autophagy and the Immune System
Kuballa, P., Nolte, W. M., Castoreno, A. B., & Xavier, R. J. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074948 · Cited by 328 · see citing works
LC3 and GATE-16 N Termini Mediate Membrane Fusion Processes Required for Autophagosome Biogenesis
Weidberg, H., Shpilka, T., Shvets, E., Abada, A., Shimron, F., & Elazar, Z. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.02.006 · Cited by 326 · see citing works
“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).”
BackgroundThe induction of autophagy by γ‐radiation contributes to the radioresistance of glioma stem cells
Lomonaco, S. L., Finniss, S., Xiang, C., deCarvalho, A. C., Umansky, F., Kalkanis, S. N., Mikkelsen, T., & Brodie, C. (2009) · International Journal of Cancer · doi:10.1002/ijc.24402 · Cited by 322 · see citing works
“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 322 · see citing works
“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 317 · see citing works
Chung, T., Phillips, A. R., & Vierstra, R. D. (2010) · The Plant Journal · doi:10.1111/j.1365-313x.2010.04166.x · Cited by 315 · see citing works
Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy
Nakatogawa, H. (2013) · Essays in Biochemistry · doi:10.1042/bse0550039 · Cited by 315 · see citing works
“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 318 · see citing works
Posttranslational modification of autophagy-related proteins in macroautophagy
Xie, Y., Kang, R., Sun, X., Zhong, M., Huang, J. L., Klionsky, D. J., & Tang, D. (2014) · Autophagy · doi:10.4161/15548627.2014.984267 · Cited by 309 · see citing works
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 · see citing works
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 310 · see citing works
“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 303 · see citing works
“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 302 · see citing works
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 · see citing works
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 281 · see citing works
“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 274 · see citing works
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 276 · see citing works
Non‐autophagic roles of autophagy‐related proteins
Subramani, S. E., & Malhotra, V. (2013) · EMBO Reports · doi:10.1038/embor.2012.220 · Cited by 276 · see citing works
Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer
Bruntz, R. C., Lindsley, C. W., & Brown, H. A. (2014) · Pharmacological Reviews · doi:10.1124/pr.114.009217 · Cited by 275 · see citing works
“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 · see citing works
“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 · see citing works
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 271 · see citing works
“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 · see citing works
“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 269 · see citing works
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 · see citing works
“[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 262 · see citing works
“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 · see citing works
“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 266 · see citing works
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 257 · see citing works
“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 255 · see citing works
“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 247 · see citing works
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 244 · see citing works
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 243 · see citing works
“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 243 · see citing works
- 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
- Health Sciences › Medicine › Epidemiology › 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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