LC3, an Autophagosome Marker, Can be Incorporated into Protein Aggregates Independent of Autophagy: Caution in the Interpretation of LC3 Localization
Open accessAbstract
Autophagy is an intracellular bulk degradation system, through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Microtuble-associated protein light chain 3 (LC3), a mammalian homolog of yeast Atg8, has been used as a specific marker to monitor autophagy. Upon induction of autophagy, LC3 is conjugated to phosphatidylethanolamine and targeted to autophagic membranes. Therefore, changes in LC3 localization have been used to measure autophagy. However, this method has some limitations. In this report, we show that LC3 protein tends to aggregate in an autophagy-independent manner when it is transiently overexpressed by transfection. In addition, LC3 is easily incorporated into intracellular protein aggregates, such as inclusion bodies induced by polyQ expression or formed in autophagy-deficient hepatocytes, neurons, or senescent fibroblasts. These findings demonstrate that punctate dots containing LC3 do not always represent autophagic structures. Therefore, LC3 localization should be carefully interpreted, particularly if LC3 is overexpressed by transient transfection or if aggregates are formed within cells.
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LC3-positive punctate dots do not always represent autophagic structures, particularly in cells presenting protein aggregates.
“However, it is important to be cautious with the interpretation of the LC3 staining, as studies previously demonstrated that LC3-positive punctate dots do not always represent autophagic structures, particularly in cells presenting protein aggregates [67].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [67]
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High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy
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Chapter 1 Monitoring Autophagy in Mammalian Cultured Cells through the Dynamics of LC3
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Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2–mediated suppression of mTORC1
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“Microtubuleassociated protein 1A/1B-light chain 3 (LC3-I), the mammalian homolog of the yeast protein Atg8 (Aut7/Apg8p), is conjugated to phosphatidylethanolamine to form LC3-phosphatidylethanolamine conjugate (LC3-II), which is recruited to autophagosomal membranes (13, 14).”
BackgroundRapid and efficient clathrin-mediated endocytosis revealed in genome-edited mammalian cells
Doyon, J., Zeitler, B., Cheng, J., Cheng, A. T., Cherone, J. M., Santiago, Y., Lee, A. H., Vo, T. D., Doyon, Y., Miller, J. C., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2175 · Cited by 244 · see citing works
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“LC3 reveals the specific labeling of autophagosome membranes in addition to the cytoplasmic labeling, which could be incorporated into protein aggregates independent of autophagy (41).”
BackgroundFujita, K.-I., Maeda, D., Xiao, Q., & Srinivasula, S. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014156108 · Cited by 225 · see citing works
“able quantification of dot formation in autophagy-activated cells (21).”
BackgroundThe Pancreatitis-induced Vacuole Membrane Protein 1 Triggers Autophagy in Mammalian Cells
Ropolo, A., Grasso, D., Pardo, R., Sacchetti, M. L., Archange, C., Re, A. L., Seux, M., Nowak, J., Gonzalez, C. D., Iovanna, J. L., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706956200 · Cited by 223 · see citing works
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New Autophagy Reporter Mice Reveal Dynamics of Proximal Tubular Autophagy
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Acetylated microtubules are required for fusion of autophagosomes with lysosomes
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“Caution is required to interpret the results from immunoblot since the LC3 levels are dynamically altered [8].”
BackgroundCCT2 is an aggrephagy receptor for clearance of solid protein aggregates
Ma, X., Lu, C., Chen, Y., Li, S., Ma, N., Tao, X., Li, Y., Wang, J., Zhou, M., Yan, Y., et al. (2022) · Cell · doi:10.1016/j.cell.2022.03.005 · Cited by 206 · see citing works
The Autophagy Lysosomal Pathway and Neurodegeneration
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“Interestingly, although LC3 remains the most specific known marker of autophagosomes, LC3-independent forms of autophagy have been described (Kuma et al. 2007; Szalai et al. 2015; Engedal and Seglen 2016).”
BackgroundAutophagy: Regulation and role in disease
Meijer, A. J., & Codogno, P. (2009) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360903044068 · Cited by 199 · see citing works
Autophagy and p62 in Cardiac Proteinopathy
Zheng, Q., Su, H., Ranek, M. J., & Wang, X. (2011) · Circulation Research · doi:10.1161/circresaha.111.244707 · Cited by 193 · see citing works
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Organic fluorescent probes for monitoring autophagy in living cells
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Autophagy inhibition enabled efficient photothermal therapy at a mild temperature
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Regulation of Autophagy By Signaling Through the Atg1/ULK1 Complex
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LRRC25 inhibits type I IFN signaling by targeting ISG15‐associated RIG‐I for autophagic degradation
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“LC3 is a well-characterized marker of the autophagy process (Kuma et al , 2007).”
Autophagy in tumor suppression and cancer therapy
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Human WIPI‐1 puncta‐formation: A novel assay to assess mammalian autophagy
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“Recently, difficulties in using LC3-GFP as a marker for autophagy were noticed [21].”
BackgroundUtilizing flow cytometry to monitor autophagy in living mammalian cells
Shvets, E., Fass, E., & Elazar, Z. (2008) · Autophagy · doi:10.4161/auto.5939 · Cited by 163 · see citing works
Riley, B. E., Kaiser, S. E., Shaler, T. A., Ng, A., Hara, T., Hipp, M. S., Lage, K., Xavier, R. J., Ryu, K., Taguchi, K., et al. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201005012 · Cited by 162 · see citing works
“in increased Ub species in either soluble or insoluble fractions, which is consistent with previous studies showing the absence of Ubpositive inclusions in unstressed Atg5 KO cells (Szeto et al., 2006; Kuma et al., 2007).”
ResultSelf-citationChapter 2 Methods for Monitoring Autophagy Using GFP‐LC3 Transgenic Mice
Mizushima, N. (2009) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)03602-1 · Cited by 160 · see citing works
Self-citationMeasurement of Autophagy in Cells and Tissues
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“The pitfall for this approach is that ectopically expressed GFP-LC3B often forms aggregates that are difficult to distinguish from the GFP-LC3B puncta, the characteristic subcellular structures that refer to autophagosomes under a fluorescence microscope.(9) Electron microscopy, the most conventional—-yet still a stan…”
BackgroundMiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9
Yang, J., Chen, D., He, Y., Meléndez, A., Feng, Z., Hong, Q., Bai, X., Li, Q., Cai, G., Wang, J., et al. (2011) · AGE · doi:10.1007/s11357-011-9324-3 · Cited by 157 · see citing works
“Autophagic flux can be measured by monitoring LC3 conversion from LC3-I to LC3-II, a wellestablished marker for autophagy, in the presence of lysosomal inhibitors (Kuma et al. 2007).”
BackgroundDiet, Autophagy, and Cancer: A Review
Singletary, K. W., & Milner, J. (2008) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-07-2917 · Cited by 157 · see citing works
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“Second, studies in HeLa cells have shown that overexpression of GFP tagged proteins (LC3) could trigger aggregate formation independently of autophagosomes formation (Kuma et al., 2007).”
BackgroundSpitzer, C., Li, F., Buono, R. A., Roschzttardtz, H., Chung, T., Zhang, M., Osteryoung, K. W., Vierstra, R. D., & Otegui, M. S. (2015) · The Plant Cell · doi:10.1105/tpc.114.135939 · Cited by 152 · see citing works
“…and Are Required for Releasing RECA-GFP-Containing Bodies To reveal the underlying autophagic mechanism responsible for plastid protein degradation, we analyzed in more detail the dynamics of the autophagic tracer GFP-ATG8 (Thompson et al., 2005; Kuma et al., 2007) in wild-type seedlings.”
BackgroundAutophagy in cardiovascular disease
Martinet, W., Knaapen, M., Kockx, M. M., & Meyer, G. R. Y. D. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.08.004 · Cited by 152 · see citing works
Autophagy and adaptive immunity
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Assays to monitor autophagy in Drosophila
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“In some instances Atg8 proteins can form aggregates that appear similar to autophagic vesicles, particularly when expressed at high levels or in the presence of other aggregate-prone proteins [22, 23].”
BackgroundDisruption of Neuronal Autophagy by Infected Microglia Results in Neurodegeneration
Alirezaei, M., Kiosses, W. B., Flynn, C. T., Brady, N. R., & Fox, H. S. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002906 · Cited by 147 · see citing works
“The conversion of LC-I to LC3-II is correlated with the number of AV, and can be assessed by immunoblotting [10,32,33].”
BackgroundBif-1/Endophilin B1: a candidate for crescent driving force in autophagy
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“itself may cause the aggregation and formation of foci in an autophagy-independent manner, such as those that are observed when cells are transfected with GFP–LC3.(62)”
Cadmium-Induced Autophagy in Rat Kidney: An Early Biomarker of Subtoxic Exposure
Chargui, A., Zekri, S., Jacquillet, G., Rubera, I., Ilié, M., Belaïd, A., Duranton, C., Tauc, M., Hofman, P. M., Poujeol, P., et al. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr031 · Cited by 142 · see citing works
“4C) and LC3 can also be incorporated into ubiquitinated inclusion bodies, independently of autophagy (Kuma et al. 2007).”
Newman, R. A., Kondo, Y., Yokoyama, T., Dixon, S., Cartwright, C., Chan, D., Johansen, M. J., & Yang, P. (2007) · Integrative Cancer Therapies · doi:10.1177/1534735407309623 · Cited by 141 · see citing works
“Therefore, GFPtagged LC3-expressing cells have been used to demonstrate induction of autophagy.(16,17) GFP-LC3 cells present a diffuse distribution under control conditions, whereas a punctuate pattern of GFP-LC3 expression is indicative of autophagy.”
MethodUpregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity
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Basal Autophagy Decreased During the Differentiation of Human Adult Mesenchymal Stem Cells
Oliver, L., Hue, E. S., Priault, M., & Vallette, F. M. (2012) · Stem Cells and Development · doi:10.1089/scd.2012.0124 · Cited by 141 · see citing works
“…an accumulation of LC3-II has been observed when the process of autophagosome–lyso-some fusion or downstream protein degradation is impaired [26], to exclude this possibility that the accumulation of LC3-II was also determined in the presence of the inhibitor of vacuolar H( + )-ATPase…”
Reduced apoptosis correlates with enhanced autophagy in synovial tissues of rheumatoid arthritis
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“Beclin-1 is critical for the nucleation phase of autophagy, and it promotes the conversion of LC3-I to LC3-II to induce autophagy (Komatsu et al., 2007; Kuma et al., 2007).”
BackgroundThe Parkinsonian Mimetic, MPP+, Specifically Impairs Mitochondrial Transport in Dopamine Axons
Kim‐Han, J. S., Antenor‐Dorsey, J. A. V., & O’Malley, K. L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0711-11.2011 · Cited by 133 · see citing works
“Chris Weihl, Washington University) at DIV5-6 as previously reported (Kuma et al., 2007).”
MethodCullinane, M., Gong, L., Li, X., Adler, N. R. L., Tra, T., Wolvetang, E. J., Prescott, M., Boyce, J. D., Devenish, R. J., & Adler, B. (2008) · Autophagy · doi:10.4161/auto.6246 · Cited by 132 · see citing works
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“It has been described that GFP-LC3 tends to aggregate in an autophagy-independent manner when it is transiently overexpressed by transfection (Kuma et al., 2007).”
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Methods for the Detection of Autophagy in Mammalian Cells
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“It has been reported that larger LC3 punctate structures are detected when the autophagosome-lysosome fusion is blocked, which is possibly due to autophagosome-autophagosome fusion (Kuma et al., 2007).”
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“In this context, it has been postulated recently that the number of autophagosomes detected in tissues can be used as a measure of autophagic activity.(49) However, despite an exponential growth in the number of publications on the subject, the role of autophagy in cancer progression remains controversial.”
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Autophagy in Neurite Injury and Neurodegeneration: In Vitro and In Vivo Models
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“Special considerations for protein aggregation disease—A recent study demonstrated that cytosolic protein aggregates can be labeled with GFP-LC3 even in the absence of progression to autophagy (Kuma et al., 2007).”
BackgroundNovel Insights into the Interplay between Apoptosis and Autophagy
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Quality control of plant peroxisomes in organ specific manner via autophagy
Yoshimoto, K., Shibata, M., Kondo, M., Oikawa, K., Sato, M., Toyooka, K., Shirasu, K., Nishimura, M., & Ohsumi, Y. (2014) · Journal of Cell Science · doi:10.1242/jcs.139709 · Cited by 114 · see citing works
- Authors
- Kuma, A., Matsui, M., & Mizushima, N.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2007-07-16
- Volume
- 3
- Issue
- 4
- Pages
- 323-328
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- OpenAlex
- W2037967087
- Semantic Scholar
- 5d5fb30a41e0817fd56223097de7b548940031cf
- Cited by
- 555
- References
- 35
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 21 · 2023: 24 · 2022: 29 · 2021: 42 · 2020: 28 · 2019: 37 · 2018: 29 · 2017: 38 · 2016: 33 · 2015: 25 · 2014: 34 · 2013: 32 · 2012: 28
- FWCI
- 22.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Autophagy (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Cell Science Research Foundation
- Kato Memorial Bioscience Foundation
- Japan Society for the Promotion of Science
- 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
- LC3, protein aggregation, inclusion bodies, polyglutamine, senescent fibroblasts, autophagy monitoring
- MeSH terms
- Animals, Antigens, Viral, Tumor, Autophagy, Cell Line, Transformed, Cell Transformation, Viral, Cells, Cultured, Fibroblasts, Immunohistochemistry, Mice, Inbred C57BL, Mice, Transgenic, Microtubule-Associated Proteins, Phosphatidylethanolamines, Proteins, Simian virus 40, Transfection, Biomarkers, Artifacts, Mice, Knockout, Green Fluorescent Proteins, Mice
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