- Timeline
- Published:
Autophagy: from phenomenology to molecular understanding in less than a decade
Nature Reviews Molecular Cell Biology volume 8, pages 931–937 (2007)Cite this article
-
14k Accesses
-
1751 Citations
-
19 Altmetric
Abstract
In 2000, it was suggested to me that "Autophagy will be the wave of the future; it will become the new apoptosis." Few people would have agreed at the time, but this statement turned out to be prophetic, and this process of 'self-eating' rapidly exploded as a research field, as scientists discovered connections to cancer, neurodegeneration and even lifespan extension. Amazingly, the molecular breakthroughs in autophagy have taken place during only the past decade.
This is a preview of subscription content, access via your institution
Access options
Subscription info for Japanese customers
We have a dedicated website for our Japanese customers. Please go to natureasia.com to subscribe to this journal.
Prices may be subject to local taxes which are calculated during checkout
References
de Duve, C., Pressman, B. C., Gianetto, R., Wattiaux, R. & Appelmans, F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J. 60, 604–617 (1955).
Ashford, T. P. & Porter, K. R. Cytoplasmic components in hepatic cell lysosomes. J. Cell Biol. 12, 198–202 (1962).
Clark, S. L. Jr. Cellular differentiation in the kidneys of newborn mice studied with the electron microscope. J. Biophys. Biochem. Cytol. 3, 349–362 (1957).
de Duve, C. & Wattiaux, R. Functions of lysosomes. Annu. Rev. Physiol. 28, 435–492 (1966).
Novikoff, A. B. The proximal tubule cell in experimental hydronephrosis. J. Biophys. Biochem. Cytol. 6, 136–138 (1959).
Kopitz, J., Kisen, G. O., Gordon, P. B., Bohley, P. & Seglen, P. O. Nonselective autophagy of cytosolic enzymes by isolated rat hepatocytes. J. Cell Biol. 111, 941–953 (1990).
Fengsrud, M., Lunde Sneve, M., Øverbye, A. & Seglen, P. O. in Autophagy (ed. Klionsky, D. J.) 11–25 (Landes Bioscience, Texas, 2004).
Seglen, P. O. in Lysosomes: Their Role in Protein Breakdown (eds Glaumann, H. & Ballard, F. J.) 371–414 (Academic Press, Florida, 1987).
Gordon, P. B. & Seglen, P. O. Prelysosomal convergence of autophagic and endocytic pathways. Biochem. Biophys. Res. Commun. 151, 40–47 (1988).
Mizushima, N. et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J. Cell Biol. 152, 657–668 (2001).
Takeshige, K., Baba, M., Tsuboi, S., Noda, T. & Ohsumi, Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol. 119, 301–311 (1992).
Kim, J., Huang, W. -P., Stromhaug, P. E. & Klionsky, D. J. Convergence of multiple autophagy and cytoplasm to vacuole targeting components to a perivacuolar membrane compartment prior to de novo vesicle formation. J. Biol. Chem. 277, 763–773 (2002).
Suzuki, K. et al. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20, 5971–5981 (2001).
Deter, R. L., Baudhuin, P. & de Duve, C. Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J. Cell Biol. 35, C11–C16 (1967).
Pfeifer, U. Inhibition by insulin of the physiological autophagic breakdown of cell organelles. Acta Biol. Med. Ger. 36, 1691–1694 (1977).
Mortimore, G. E. & Schworer, C. M. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature 270, 174–176 (1977).
Seglen, P. O. & Gordon, P. B. 3-methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl Acad. Sci. USA 79, 1889–1892 (1982).
Holen, I., Gordon, P. B. & Seglen, P. O. Protein kinase-dependent effects of okadaic acid on hepatocytic autophagy and cytoskeletal integrity. Biochem. J. 284, 633–636 (1992).
Kunz, J. et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585–596 (1993).
Blommaart, E. F., Luiken, J. J., Blommaart, P. J., van Woerkom, G. M. & Meijer, A. J. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J. Biol. Chem. 270, 2320–2326 (1995).
Blommaart, E. F., Krause, U., Schellens, J. P., Vreeling-Sindelarova, H. & Meijer, A. J. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur. J. Biochem. 243, 240–246 (1997).
Petiot, A., Ogier-Denis, E., Blommaart, E. F., Meijer, A. J. & Codogno, P. Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J. Biol. Chem. 275, 992–998 (2000).
Arico, S. et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 276, 35243–35246 (2001).
Noda, T. & Ohsumi, Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273, 3963–3966 (1998).
Bolender, R. P. & Weibel, E. R. A morphometric study of the removal of phenobarbital-induced membranes from hepatocytes after cessation of treatment. J. Cell Biol. 56, 746–761 (1973).
Beaulaton, J. & Lockshin, R. A. Ultrastructural study of the normal degeneration of the intersegmental muscles of Anthereae polyphemus and Manduca sexta (Insecta, Lepidoptera) with particular reference of cellular autophagy. J. Morphol. 154, 39–57 (1977).
Veenhuis, M., Douma, A., Harder, W. & Osumi, M. Degradation and turnover of peroxisomes in the yeast Hansenula polymorpha induced by selective inactivation of peroxisomal enzymes. Arch. Microbiol. 134, 193–203 (1983).
Lemasters, J. J. et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta 1366, 177–196 (1998).
Elmore, S. P., Qian, T., Grissom, S. F. & Lemasters, J. J. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J. 15, 2286–2287 (2001).
Xue, L., Fletcher, G. C. & Tolkovsky, A. M. Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr. Biol. 11, 361–365 (2001).
Harding, T. M., Morano, K. A., Scott, S. V. & Klionsky, D. J. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J. Cell Biol. 131, 591–602 (1995).
Baba, M., Osumi, M., Scott, S. V., Klionsky, D. J. & Ohsumi, Y. Two distinct pathways for targeting proteins from the cytoplasm to the vacuole/lysosome. J. Cell Biol. 139, 1687–1695 (1997).
Harding, T. M., Hefner-Gravink, A., Thumm, M. & Klionsky, D. J. Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway. J. Biol. Chem. 271, 17621–17624 (1996).
Scott, S. V., Baba, M., Ohsumi, Y. & Klionsky, D. J. Aminopeptidase I is targeted to the vacuole by a nonclassical vesicular mechanism. J. Cell Biol. 138, 37–44 (1997).
Scott, S. V. et al. Cytoplasm-to-vacuole targeting and autophagy employ the same machinery to deliver proteins to the yeast vacuole. Proc. Natl Acad. Sci. USA 93, 12304–12308 (1996).
Hutchins, M. U. & Klionsky, D. J. Vacuolar localization of oligomeric α-mannosidase requires the cytoplasm to vacuole targeting and autophagy pathway components in Saccharomyces cerevisiae. J. Biol. Chem. 276, 20491–20498 (2001).
Klionsky, D. J., Cueva, R. & Yaver, D. S. Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway. J. Cell Biol. 119, 287–299 (1992).
Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993).
Klionsky, D. J. et al. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545 (2003).
Matsuura, A., Tsukada, M., Wada, Y. & Ohsumi, Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192, 245–250 (1997).
Kabeya, Y., Kawamata, T., Suzuki, K. & Ohsumi, Y. Cis1/Atg31 is required for autophagosome formation in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 356, 405–410 (2007).
Hutchins, M. U., Veenhuis, M. & Klionsky, D. J. Peroxisome degradation in Saccharomyces cerevisiae is dependent on machinery of macroautophagy and the Cvt pathway. J. Cell Sci. 112, 4079–4087 (1999).
Zhang, Y. et al. The role of autophagy in mitochondria maintenance: characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy 3, 337–346 (2007).
Klionsky, D. J. The molecular machinery of autophagy: unanswered questions. J. Cell Sci. 118, 7–18 (2005).
Klionsky, D. J., Cuervo, A. M. & Seglen, P. O. Methods for monitoring autophagy from yeast to human. Autophagy 3, 181–206 (2007).
Ohsumi, Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nature Rev. Mol. Cell Biol. 2, 211–216 (2001).
Mizushima, N., Sugita, H., Yoshimori, T. & Ohsumi, Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J. Biol. Chem. 273, 33889–33892 (1998).
Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).
Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).
Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).
Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).
Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).
Mathew, R. et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 21, 1367–1381 (2007).
Rikihisa, Y. Glycogen autophagosomes in polymorphonuclear leukocytes induced by Rickettsiae. Anat. Rec. 208, 319–327 (1984).
Beron, W., Gutierrez, M. G., Rabinovitch, M. & Colombo, M. I. Coxiella burnetii localizes in a Rab7-labeled compartment with autophagic characteristics. Infect. Immun. 70, 5816–5821 (2002).
Swanson, M. S. & Isberg, R. R. Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Infect. Immun. 63, 3609–3620 (1995).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).
Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).
Ogawa, M. et al. Escape of intracellular Shigella from autophagy. Science 307, 727–731 (2005).
Liang, X. H. et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 72, 8586–8596 (1998).
Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).
Tallóczy, Z., Virgin, H. W. & Levine, B. PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2, 24–29 (2006).
Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922–7927 (2005).
Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005).
Rubinsztein, D. C. et al. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1, 11–22 (2005).
Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).
Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell Biol. 25, 1025–1040 (2005).
Yu, L. et al. Regulation of an ATG7–beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004).
Sugawara, K. et al. The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8. Genes Cells 9, 611–618 (2004).
Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O. & Klionsky, D. J. Potential therapeutic applications of autophagy. Nature Rev. Drug Discov. 6, 304–312 (2007).
Gozuacik, D. & Kimchi, A. Autophagy and cell death. Curr. Top. Dev. Biol. 78, 217–245 (2007).
Meijer, A. J. & Codogno, P. Signalling and autophagy regulation in health, aging and disease. Mol. Aspects Med. 27, 411–425 (2006).
Nobukuni, T., Kozma, S. C. & Thomas, G. hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr. Opin. Cell Biol. 19, 135–141 (2007).
Gordon, P. B. & Seglen, P. O. Autophagic sequestration of [14C]sucrose, introduced into rat hepatocytes by reversible electro-permeabilization. Exp. Cell Res. 142, 1–14 (1982).
Kawamata, T. et al. Characterization of a novel autophagy-specific gene, ATG29. Biochem. Biophys. Res. Commun. 338, 1884–1889 (2005).
Stasyk, O. V. et al. Atg28, a novel coiled-coil protein involved in autophagic degradation of peroxisomes in the methylotrophic yeast Pichia pastoris. Autophagy 2, 30–38 (2006).
Bergamini, E. Autophagy: a cell repair mechanism that retards ageing and age-associated diseases and can be intensified pharmacologically. Mol. Aspects Med. 27, 403–410 (2006).
Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).
Shimizu, S. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol. 6, 1221–1228 (2004).
Liu, Y. et al. Autophagy regulates programmed cell death during the plant innate immune response. Cell 121, 567–577 (2005).
Schmid, D. & Münz, C. Immune surveillance of intracellular pathogens via autophagy. Cell Death Differ. 12, 1519–1527 (2005).
Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).
Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).
Acknowledgements
I thank P. Codogno, B. Levine, F. Meijer, N. Mizushima and P. Seglen for their comments, and apologize to those researchers whose work could not be cited due to space limitations. This work was supported by a grant from the US National Institutes of Health.
Ethics declarations
Competing interests
The author declares no competing financial interests.
Supplementary information
Supplementary information S1 (movie) | Autophagosome formation
The formation of an autophagosome is visualized by monitoring a green fluorescent protein (GFP)-ATG5 fusion protein in mouse embryonic stem cells through time-lapse video microscopy (5 minutes elapsed time). ATG5 localizes on the phagophore membrane during elongation and dissociates from the membrane upon completion of autophagosome formation. Movie provided by Noboru Mizushima (Tokyo Medical and Dental University). (AVI 599 kb)
Related links
Related links
DATABASES
Entrez Genome Project
FURTHER INFORMATION
Rights and permissions
About this article
Cite this article
Klionsky, D. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8, 931–937 (2007). https://doi.org/10.1038/nrm2245
Issue date:
DOI: https://doi.org/10.1038/nrm2245
Share this article
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
This article is cited by
-
Identification and clinical validation of diverse cell-death patterns-associated prognostic features among low-grade gliomas
- Wenyong Yang
- Hui Yu
- Liangbin Lin
Scientific Reports (2024)
-
Restrained Mitf-associated autophagy by Mulberroside A ameliorates osteoclastogenesis and counteracts OVX-Induced osteoporosis in mice
- Hong Xue
- Zhenhua Feng
- Xuewu Sun
Cell Death Discovery (2024)
-
The role of H3K27me3 methylation in cancer development
- Longjiang Di
- Wei-Guo Zhu
Genome Instability & Disease (2024)
-
Exon Sequence Analysis of the ATG5, ATG12, ATG9B Genes in Colorectal Cancer Patients During Radiotherapy
- Tuğba Mehmetoğlu Gürbüz
- Ethem Nezih Oral
- Ş. Ümit Zeybek
Indian Journal of Clinical Biochemistry (2024)
-
mTORC2: a multifaceted regulator of autophagy
- Yanan Sun
- Huihui Wang
- Yixuan Li
Cell Communication and Signaling (2023)
