Abstract
Autophagy is a highly conserved catabolic process induced under various conditions of cellular stress, which prevents cell damage and promotes survival in the event of energy or nutrient shortage and responds to various cytotoxic insults. Thus, autophagy has primarily cytoprotective functions and needs to be tightly regulated to respond correctly to the different stimuli that cells experience, thereby conferring adaptation to the ever-changing environment. It is now apparent that autophagy is deregulated in the context of various human pathologies, including cancer and neurodegeneration, and its modulation has considerable potential as a therapeutic approach.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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).
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).
Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993).
Abada, A. & Elazar, Z. Getting ready for building: signaling and autophagosome biogenesis. EMBO Rep. 15, 839–852 (2014).
Lamb, C. A., Yoshimori, T. & Tooze, S. A. The autophagosome: origins unknown, biogenesis complex. Nat. Rev. Mol. Cell Biol. 14, 759–774 (2013).
Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).
Klionsky, D. J. et al. A comprehensive glossary of autophagy-related molecules and processes (2nd edition). Autophagy 7, 1273–1294 (2011).
Hamasaki, M. et al. Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389–393 (2013).
Nascimbeni, A. C. et al. ER-plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI3P synthesis. EMBO J. 36, 2018–2033 (2017).
Karanasios, E. et al. Dynamic association of the ULK1 complex with omegasomes during autophagy induction. J. Cell Sci. 126, 5224–5238 (2013).
Manifava, M. et al. Dynamics of mTORC1 activation in response to amino acids. eLife 5, e19960 (2016).
Nishimura, T. et al. Autophagosome formation is initiated at phosphatidylinositol synthase-enriched ER subdomains. EMBO J. 36, 1719–1735 (2017).
Gonzalez, A. & Hall, M. N. Nutrient sensing and TOR signaling in yeast and mammals. EMBO J. 36, 397–408 (2017).
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
Bar-Peled, L. & Sabatini, D. M. Regulation of mTORC1 by amino acids. Trends Cell Biol. 24, 400–406 (2014).
Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).
Jung, C. H. et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992–2003 (2009).
Settembre, C., Fraldi, A., Medina, D. L. & Ballabio, A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296 (2013).
Di Malta, C. et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science 356, 1188–1192 (2017). This study describes an important mechanism by which TFEB, a major regulator of autophagy, links cellular metabolic states to the regulation of mTORC1.
Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010).
Tripathi, D. N. et al. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1. Proc. Natl Acad. Sci. USA 110, E2950–E2957 (2013).
Bakula, D. et al. WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Nat. Commun. 8, 15637 (2017).
Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).
Sakamaki, J. I. et al. Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function. Mol. Cell 66, 517–532.e9 (2017).
Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471 (2007).
Zhao, J. et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6, 472–483 (2007).
Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005). This work describes an interesting link between apoptosis and autophagy, characterizing BCL-2 as a negative regulator of both processes.
Fimia, G. M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121–1125 (2007).
Di Bartolomeo, S. et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J. Cell Biol. 191, 155–168 (2010).
Cinque, L. et al. FGF signalling regulates bone growth through autophagy. Nature 528, 272–275 (2015).
Xu, D. Q. et al. PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity. EMBO J. 35, 496–514 (2016).
Su, H. et al. VPS34 acetylation controls its lipid kinase activity and the initiation of canonical and non-canonical autophagy. Mol. Cell 67, 907–921.e7 (2017).
McKnight, N. C. et al. Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC. EMBO J. 31, 1931–1946 (2012).
Joachim, J. et al. Activation of ULK kinase and autophagy by GABARAP trafficking from the centrosome is regulated by WAC and GM130. Mol. Cell 60, 899–913 (2015).
Fan, W., Nassiri, A. & Zhong, Q. Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). Proc. Natl Acad. Sci. USA 108, 7769–7774 (2011).
Itakura, E., Kishi, C., Inoue, K. & Mizushima, N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19, 5360–5372 (2008).
Park, J. M. et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547–564 (2016).
Tan, X., Thapa, N., Liao, Y., Choi, S. & Anderson, R. A. PtdIns(4,5)P2 signaling regulates ATG14 and autophagy. Proc. Natl Acad. Sci. USA 113, 10896–10901 (2016).
Papinski, D. et al. Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Mol. Cell 53, 471–483 (2014).
Lamb, C. A. et al. TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic. EMBO J. 35, 281–301 (2016).
Shirahama-Noda, K., Kira, S., Yoshimori, T. & Noda, T. TRAPPIII is responsible for vesicular transport from early endosomes to Golgi, facilitating Atg9 cycling in autophagy. J. Cell Sci. 126, 4963–4973 (2013).
Webster, C. P. et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 35, 1656–1676 (2016).
Mi, N. et al. CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane. Nat. Cell Biol. 17, 1112–1123 (2015).
Kast, D. J., Zajac, A. L., Holzbaur, E. L., Ostap, E. M. & Dominguez, R. WHAMM directs the Arp2/3 complex to the er for autophagosome biogenesis through an actin comet tail mechanism. Curr. Biol. 25, 1791–1797 (2015).
Slobodkin, M. R. & Elazar, Z. The Atg8 family: multifunctional ubiquitin-like key regulators of autophagy. Essays Biochem. 55, 51–64 (2013).
Li, M. et al. Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates. J. Biol. Chem. 286, 7327–7338 (2011).
Woo, J., Park, E. & Dinesh-Kumar, S. P. Differential processing of Arabidopsis ubiquitin-like Atg8 autophagy proteins by Atg4 cysteine proteases. Proc. Natl Acad. Sci. USA 111, 863–868 (2014).
Kuma, A., Mizushima, N., Ishihara, N. & Ohsumi, Y. Formation of the approximately 350-kDa Apg12-Apg5. Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. J. Biol. Chem. 277, 18619–18625 (2002).
Fujioka, Y., Noda, N. N., Nakatogawa, H., Ohsumi, Y. & Inagaki, F. Dimeric coiled-coil structure of Saccharomyces cerevisiae Atg16 and its functional significance in autophagy. J. Biol. Chem. 285, 1508–1515 (2010).
Dooley, H. C. et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol. Cell 55, 238–252 (2014).
Kaufmann, A., Beier, V., Franquelim, H. G. & Wollert, T. Molecular mechanism of autophagic membrane-scaffold assembly and disassembly. Cell 156, 469–481 (2014).
Weidberg, H. et al. LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev. Cell 20, 444–454 (2011).
Ge, L. et al. Remodeling of ER-exit sites initiates a membrane supply pathway for autophagosome biogenesis. EMBO Rep. 18, 1586–1603 (2017).
Ge, L., Zhang, M. & Schekman, R. Phosphatidylinositol 3-kinase and COPII generate LC3 lipidation vesicles from the ER-Golgi intermediate compartment. eLife 3, e04135 (2014).
Graef, M., Friedman, J. R., Graham, C., Babu, M. & Nunnari, J. ER exit sites are physical and functional core autophagosome biogenesis components. Mol. Biol. Cell 24, 2918–2931 (2013). Studies in refs 54 and 55 implicate ER exit sites in the process of autophagosome biogenesis.
Tsuboyama, K. et al. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354, 1036–1041 (2016).
Nguyen, T. N. et al. Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation. J. Cell Biol. 215, 857–874 (2016).
Scherz-Shouval, R. et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26, 1749–1760 (2007).
Pengo, N., Agrotis, A., Prak, K., Jones, J. & Ketteler, R. A reversible phospho-switch mediated by ULK1 regulates the activity of autophagy protease ATG4B. Nat. Commun. 8, 294 (2017).
Sanchez-Wandelmer, J. et al. Atg4 proteolytic activity can be inhibited by Atg1 phosphorylation. Nat. Commun. 8, 295 (2017).
Cherra, S. J. 3rd et al. Regulation of the autophagy protein LC3 by phosphorylation. J. Cell Biol. 190, 533–539 (2010).
Diao, J. et al. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520, 563–566 (2015).
Itakura, E., Kishi-Itakura, C. & Mizushima, N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151, 1256–1269 (2012). This important study characterizes syntaxin 17 (STX17) as an autophagosome-associated SNARE molecule that mediates autophagosomal–lysosomal membrane fusion. STX17 may therefore serve as an endogenous marker for the mature autophagosome.
Koyama-Honda, I., Itakura, E., Fujiwara, T. K. & Mizushima, N. Temporal analysis of recruitment of mammalian ATG proteins to the autophagosome formation site. Autophagy 9, 1491–1499 (2013).
Stolz, A., Ernst, A. & Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495–501 (2014).
Olsvik, H. L. et al. FYCO1 contains a C-terminally extended, LC3A/B-preferring LC3-interacting region (LIR) motif required for efficient maturation of autophagosomes during basal autophagy. J. Biol. Chem. 290, 29361–29374 (2015).
McEwan, D. G. et al. PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol. Cell 57, 39–54 (2015).
Kim, Y. M. et al. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol. Cell 57, 207–218 (2015).
Jiang, P. et al. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol. Biol. Cell 25, 1327–1337 (2014).
Wilkinson, D. S. et al. Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Mol. Cell 57, 55–68 (2015).
Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980–989 (2013).
Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).
Kimmelman, A. C. & White, E. Autophagy and tumor metabolism. Cell Metab. 25, 1037–1043 (2017).
Apel, A., Herr, I., Schwarz, H., Rodemann, H. P. & Mayer, A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 68, 1485–1494 (2008).
Liu, D., Yang, Y., Liu, Q. & Wang, J. Inhibition of autophagy by 3-MA potentiates cisplatin-induced apoptosis in esophageal squamous cell carcinoma cells. Med. Oncol. 28, 105–111 (2011).
Shingu, T. et al. Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells. Int. J. Cancer 124, 1060–1071 (2009).
Rao, S. et al. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5, 3056 (2014).
Perera, R. M. et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).
Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).
Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).
Guo, J. Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460–470 (2011). This study describes how human cancers with activating HRAS and KRAS mutations commonly have upregulated basal autophagy that is required to maintain functional mitochondria and cell metabolism. Increased basal autophagy is required to maintain functional mitochondria and cell metabolism, thereby supporting tumour cell survival upon nutrient starvation (which often occurs in the core of the tumour mass) and consequently promoting tumorigenesis.
Zou, Z. et al. Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells. Autophagy 8, 1798–1810 (2012).
Galluzzi, L., Bravo-San Pedro, J. M., Demaria, S., Formenti, S. C. & Kroemer, G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol. 14, 247–258 (2017).
Hu, Y. L., Jahangiri, A., Delay, M. & Aghi, M. K. Tumor cell autophagy as an adaptive response mediating resistance to treatments such as antiangiogenic therapy. Cancer Res. 72, 4294–4299 (2012).
Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).
Martins, I. et al. Premortem autophagy determines the immunogenicity of chemotherapy-induced cancer cell death. Autophagy 8, 413–415 (2012).
Michaud, M. et al. An autophagy-dependent anticancer immune response determines the efficacy of melanoma chemotherapy. Oncoimmunology 3, e944047 (2014).
Parodi, M. et al. Natural Killer (NK)/melanoma cell interaction induces NK-mediated release of chemotactic High Mobility Group Box-1 (HMGB1) capable of amplifying NK cell recruitment. Oncoimmunology 4, e1052353 (2015).
Thorburn, J. et al. Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death Differ. 16, 175–183 (2009).
Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).
Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).
Kimura, T. et al. Cellular and molecular mechanism for secretory autophagy. Autophagy 13, 1084–1085 (2017).
Ponpuak, M. et al. Secretory autophagy. Curr. Opin. Cell Biol. 35, 106–116 (2015).
Lock, R., Kenific, C. M., Leidal, A. M., Salas, E. & Debnath, J. Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion. Cancer Discov. 4, 466–479 (2014).
Papandreou, M. E. & Tavernarakis, N. Autophagy and the endo/exosomal pathways in health and disease. Biotech. J. 12, 1600175 (2016).
Villarroya-Beltri, C. et al. ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat. Commun. 7, 13588 (2016).
Ruivo, C. F., Adem, B., Silva, M. & Melo, S. A. The biology of cancer exosomes: insights and new perspectives. Cancer Res. 77, 6480–6488 (2017).
Kiyono, K. et al. Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res. 69, 8844–8852 (2009).
Catalano, M. et al. Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells. Mol. Oncol. 9, 1612–1625 (2015).
Lv, Q. et al. DEDD interacts with PI3KC3 to activate autophagy and attenuate epithelial-mesenchymal transition in human breast cancer. Cancer Res. 72, 3238–3250 (2012).
Qiang, L. et al. Regulation of cell proliferation and migration by p62 through stabilization of Twist1. Proc. Natl Acad. Sci. USA 111, 9241–9246 (2014).
Gugnoni, M. et al. Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy. Oncogene 36, 667–677 (2017).
Peng, Y. F. et al. Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells. Autophagy 9, 2056–2068 (2013).
Cai, Q., Yan, L. & Xu, Y. Anoikis resistance is a critical feature of highly aggressive ovarian cancer cells. Oncogene 34, 3315–3324 (2015).
Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).
Avivar-Valderas, A. et al. Regulation of autophagy during ECM detachment is linked to a selective inhibition of mTORC1 by PERK. Oncogene 32, 4932–4940 (2013).
Sequeira, S. J. et al. Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation. PloS ONE 2, e615 (2007).
Chen, N. & Debnath, J. IkappaB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway. Autophagy 9, 1214–1227 (2013).
Buchheit, C. L., Angarola, B. L., Steiner, A., Weigel, K. J. & Schafer, Z. T. Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration. Cell Death Differ 22, 1275–1286 (2015).
Delgado, M. & Tesfaigzi, Y. BH3-only proteins, Bmf and Bim, in autophagy. Cell Cycle 12, 3453–3454 (2013).
Luo, S. et al. Bim inhibits autophagy by recruiting Beclin 1 to microtubules. Mol. Cell 47, 359–370 (2012).
Sharifi, M. N. et al. Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of paxillin with LC3. Cell Rep. 15, 1660–1672 (2016).
Sandilands, E. et al. Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling. Nat. Cell Biol. 14, 51–60 (2011).
Belaid, A. et al. Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability. Cancer Res. 73, 4311–4322 (2013).
Yoshida, T., Tsujioka, M., Honda, S., Tanaka, M. & Shimizu, S. Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF. Oncotarget 7, 34420–34429 (2016).
Ma, Z., Myers, D. P., Wu, R. F., Nwariaku, F. E. & Terada, L. S. p66Shc mediates anoikis through RhoA. J. Cell Biol. 179, 23–31 (2007).
Gordon, B. S. et al. RhoA modulates signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in mammalian cells. Cell. Signal. 26, 461–467 (2014).
Cullup, T. et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat. Genet. 45, 83–87 (2013).
Vantaggiato, C. et al. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. Brain 136, 3119–3139 (2013).
Saitsu, H. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat. Genet. 45, 445–449 (2013).
Dikic, I. Proteasomal and autophagy degradation systems. Annu. Rev. Biochem. 86, 193–224 (2017).
Karsli-Uzunbas, G. et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927 (2014).
Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
Gan-Or, Z., Dion, P. A. & Rouleau, G. A. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11, 1443–1457 (2015).
Trinh, J. & Farrer, M. Advances in the genetics of Parkinson disease. Nat. Rev. Neurol. 9, 445–454 (2013).
Moors, T. et al. Lysosomal dysfunction and alpha-synuclein aggregation in Parkinson’s disease: diagnostic links. Movement Disord. 31, 791–801 (2016).
Dijkstra, A. A. et al. Evidence for immune response, axonal dysfunction and reduced endocytosis in the substantia nigra in early stage Parkinson’s disease. PloS ONE 10, e0128651 (2015).
Elstner, M. et al. Expression analysis of dopaminergic neurons in Parkinson’s disease and aging links transcriptional dysregulation of energy metabolism to cell death. Acta Neuropathol. 122, 75–86 (2011).
Mutez, E. et al. Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson’s disease. Neurobiol. Dis. 63, 165–170 (2014).
Jackson, K. L. et al. p62 pathology model in the rat substantia nigra with filamentous inclusions and progressive neurodegeneration. PloS ONE 12, e0169291 (2017).
Seibenhener, M. L. et al. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol. Cell. Biol. 24, 8055–8068 (2004).
Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131–24145 (2007).
Lim, J. et al. Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet. 11, e1004987 (2015).
Ordureau, A. et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol. Cell 56, 360–375 (2014). Employing quantitative proteomics and live-cell imaging, this study comprehensively dissects the regulatory steps by which PINK1-mediated phosphorylation of Parkin and ubiquitin triggers the recruitment of Parkin to damaged mitochondria and reveals a feedforward mechanism that is responsible for the observed effects.
Shiba-Fukushima, K. et al. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 10, e1004861 (2014).
Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).
Walden, H. & Muqit, M. M. Ubiquitin and Parkinson’s disease through the looking glass of genetics. Biochem. J. 474, 1439–1451 (2017).
Koentjoro, B., Park, J. S. & Sue, C. M. Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson’s disease. Sci. Rep. 7, 44373 (2017).
Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).
Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015). This study shows that mutations in TBK1 affecting the post-translational modification of the autophagy receptor cause a neurodegenerative disease, thus highlighting not only the importance of autophagy in neurodegeneration but also the crucial role of phosphorylation of autophagy receptors.
Lee, J. K., Shin, J. H., Lee, J. E. & Choi, E. J. Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1852, 2517–2524 (2015).
Moore, A. S. & Holzbaur, E. L. Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. Proc. Natl Acad. Sci. USA 113, E3349–E3358 (2016).
Heo, J. M., Ordureau, A., Paulo, J. A., Rinehart, J. & Harper, J. W. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol. Cell 60, 7–20 (2015).
Matsumoto, G., Shimogori, T., Hattori, N. & Nukina, N. TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation. Hum. Mol. Genet. 24, 4429–4442 (2015).
Richter, B. et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc. Natl Acad. Sci. USA 113, 4039–4044 (2016).
Thurston, T. L., Wandel, M. P., von Muhlinen, N., Foeglein, A. & Randow, F. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414–418 (2012).
Gomes, L. C. & Dikic, I. Autophagy in antimicrobial immunity. Mol. Cell 54, 224–233 (2014).
Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011).
Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456, 264–268 (2008).
Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005).
Loi, M. et al. Macroautophagy proteins control MHC Class I levels on dendritic cells and shape anti-viral CD8(+) T cell responses. Cell Rep. 15, 1076–1087 (2016).
Wei, J. et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17, 277–285 (2016).
Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).
Rockel, J. S. & Kapoor, M. Autophagy: controlling cell fate in rheumatic diseases. Nat. Rev. Rheumatol. 12, 517–531 (2016).
Ma, Y., Galluzzi, L., Zitvogel, L. & Kroemer, G. Autophagy and cellular immune responses. Immunity 39, 211–227 (2013).
Criollo, A. et al. The IKK complex contributes to the induction of autophagy. EMBO J 29, 619–631 (2010).
Niso-Santano, M. et al. Direct molecular interactions between Beclin 1 and the canonical NFkappaB activation pathway. Autophagy 8, 268–270 (2012).
Copetti, T., Bertoli, C., Dalla, E., Demarchi, F. & Schneider, C. p65/RelA modulates BECN1 transcription and autophagy. Mol. Cell. Biol. 29, 2594–2608 (2009).
Djavaheri-Mergny, M. et al. NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. J. Biol. Chem. 281, 30373–30382 (2006).
Schlottmann, S. et al. Prolonged classical NF-kappaB activation prevents autophagy upon E. coli stimulation in vitro: a potential resolving mechanism of inflammation. Mediators Inflamm. 2008, 725854 (2008).
Criollo, A. et al. Autophagy is required for the activation of NFkappaB. Cell Cycle 11, 194–199 (2012).
Kim, J. E. et al. Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. Cell. Signal. 22, 1645–1654 (2010).
Niida, M., Tanaka, M. & Kamitani, T. Downregulation of active IKK beta by Ro52-mediated autophagy. Mol. Immunol. 47, 2378–2387 (2010).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004). This seminal work shows that induction of autophagy suppresses intracellular survival of mycobacteria, thus acting as an innate defence mechanism against intracellular pathogens.
Noad, J. et al. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-kappaB. Nat. Microbiol 2, 17063 (2017).
van Wijk, S. J. L. et al. Linear ubiquitination of cytosolic Salmonella Typhimurium activates NF-kappaB and restricts bacterial proliferation. Nat. Microbiol 2, 17066 (2017).
Neumann, Y. et al. Intracellular Staphylococcus aureus eludes selective autophagy by activating a host cell kinase. Autophagy 12, 2069–2084 (2016).
Nguyen, L. et al. Role of protein kinase G in growth and glutamine metabolism of Mycobacterium bovis BCG. J. Bacteriol. 187, 5852–5856 (2005).
Real, E. et al. Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes. Nat. Microbiol. 3, 17–25 (2018).
Devenish, R. J. & Lai, S. C. Autophagy and burkholderia. Immunol. Cell Biol. 93, 18–24 (2015).
Rui, Y. N. et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell Biol. 17, 262–275 (2015).
Chu, C. T. et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat. Cell Biol. 15, 1197–1205 (2013).
Sentelle, R. D. et al. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat. Chem. Biol. 8, 831–838 (2012).
Pasquier, B. Autophagy inhibitors. Cell. Mol. Life Sci. 73, 985–1001 (2016).
Egan, D. F. et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol. Cell 59, 285–297 (2015).
Petherick, K. J. et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J. Biol. Chem. 290, 28726 (2015).
Bago, R. et al. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem. J. 463, 413–427 (2014).
Dowdle, W. E. et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat. Cell Biol. 16, 1069–1079 (2014).
Ronan, B. et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol. 10, 1013–1019 (2014).
Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013). To avoid the pleiotropic effects of conventional autophagy inducers, Shoji-Kawata et al. design a cell-permeable peptide, Tat–Beclin 1, which comprises the HIV-1 Tat protein transduction domain (PTD) attached to a fragment derived from the autophagy inducer Beclin 1. TAT–Beclin 1 effectively clears protein aggregates and improves the clinical outcome of mice infected with the West Nile virus.
Wu, W. et al. Co-targeting IGF-1 R and autophagy enhances the effects of cell growth suppression and apoptosis induced by the IGF-1 R Inhibitor NVP-AEW541 in triple-negative breast cancer cells. PloS ONE 12, e0169229 (2017).
Akin, D. et al. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10, 2021–2035 (2014).
Bove, J., Martinez-Vicente, M. & Vila, M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nature Rev. Neurosci. 12, 437–452 (2011).
Liu, Z. et al. Sesamol induces human hepatocellular carcinoma cells apoptosis by impairing mitochondrial function and suppressing autophagy. Sci. Rep. 7, 45728 (2017).
Buttner, S. et al. Spermidine protects against alpha-synuclein neurotoxicity. Cell Cycle 13, 3903–3908 (2014).
Jiang, T. F. et al. Curcumin ameliorates the neurodegenerative pathology in A53T alpha-synuclein cell model of Parkinson’s disease through the downregulation of mTOR/p70S6K signaling and the recovery of macroautophagy. J. Neuroimmune Pharmacol 8, 356–369 (2013).
Macedo, D. et al. (Poly)phenols protect from alpha-synuclein toxicity by reducing oxidative stress and promoting autophagy. Hum. Mol. Genet. 24, 1717–1732 (2015).
Filomeni, G. et al. Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson’s disease. Neurobiol. Aging 33, 767–785 (2012).
Efferth, T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin. Cancer Biol. 46, 65–83 (2017).
Hua, F., Shang, S. & Hu, Z. W. Seeking new anti-cancer agents from autophagy-regulating natural products. J. Asian Nat. Prod. Res. 19, 305–313 (2017).
Yang, Z. et al. Fluvastatin prevents lung adenocarcinoma bone metastasis by triggering autophagy. EBioMedicine 19, 49–59 (2017).
Zhou, X. et al. Elaborating the role of natural products on the regulation of autophagy and their potentials in breast cancer therapy. Cancer Drug Targets. https://doi.org/10.2174/1568009617666170330124819 (2017).
Ji, H. F. & Shen, L. The multiple pharmaceutical potential of curcumin in Parkinson’s disease. CNS Neurol. Disord. Drug Targets 13, 369–373 (2014).
Mukhopadhyay, S. et al. Clinical relevance of autophagic therapy in cancer: Investigating the current trends, challenges, and future prospects. Crit. Rev. Clin. Lab. Sci. 53, 228–252 (2016).
Towers, C. G. & Thorburn, A. Therapeutic targeting of autophagy. EBioMedicine 14, 15–23 (2016).
Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).
Nah, J., Yuan, J. & Jung, Y. K. Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach. Molecules Cells 38, 381–389 (2015).
Harris, H. & Rubinsztein, D. C. Control of autophagy as a therapy for neurodegenerative disease. Nature Rev. Neurol. 8, 108–117 (2011).
Boland, B. et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J. Neurosci. 28, 6926–6937 (2008).
Jo, E. K., Yuk, J. M., Shin, D. M. & Sasakawa, C. Roles of autophagy in elimination of intracellular bacterial pathogens. Front. Immunol. 4, 97 (2013).
Kim, T. S. et al. Ohmyungsamycins promote antimicrobial responses through autophagy activation via AMP-activated protein kinase pathway. Sci. Rep. 7, 3431 (2017).
Acknowledgements
The authors thank D. Hoeller and O. Shatz for their constructive discussions, comments and help with figures. The authors apologize to all scientists whose important contributions were not referenced in this review owing to space limitations. I.D. is supported by the Deutsche Forschungsgemeinschaft-funded Collaborative Research Centre on Selective Autophagy (SFB 1177), the European Research Council (ERC) advanced grant (Agreement No. 742720), the LOEWE program Ubiquitin Networks (Ub-Net) and the LOEWE Center for Gene and Cell Therapy Frankfurt (CGT). Z.E. is supported in part by the Israeli Science Foundation (Grant 1247/15), the Legacy Heritage Fund (Grant 1935/16) and the Minerva foundation with funding from the Federal German Ministry for Education and Research.
Competing interests
The authors declare no competing interests.
Author information
Authors and Affiliations
Contributions
Both authors contributed equally to this work (researching data for the article, discussion of content, writing and editing).
Corresponding authors
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Glossary
- Contact sites
-
Interorganellar connections with distinct biochemical properties and a characteristic set of proteins that function as signalling hot spots.
- TSC2 (tuberous sclerosis 2) complex
-
Complex that is part of TSC that acts as a GTPase accelerating protein (GAP) for GTP-binding protein RHEB; because GDP-loaded RHEB is unable to activate mTORC1, TSC effectively shuts off mTORC1 signalling.
- Raptor
-
Scaffold protein unique to mTORC1 (not present in mTORC2); binds substrates as well as regulators
- FOXO (forkhead box O) proteins
-
Family of transcription factors activated in response to cell stress; they regulate genes involved in cellular energy production, oxidative stress resistance, cell viability and proliferation.
- JNK
-
Member of the MAPK family activated by extracellular signals; associated with several pathological conditions, including neurodegenerative diseases, inflammation and cancer.
- E1
-
Ubiquitin (Ub)-activating enzyme; first enzyme in the E1–E2–E3 ubiquitylation cascade that activates Ub in an ATP-dependent manner.
- E3
-
Ubiquitin (Ub)-ligating enzyme; cooperates with E2 to attach Ub to a lysine residue in the target protein. Only component of the Ub machinery that interacts with the target, thus conferring substrate specificity to the reaction.
- E2
-
Ubiquitin (Ub)-conjugating enzyme; takes over activated Ub from E1 and hands it over to E3. Plays a key role in defining the linkage type of Ub conjugation when chains of multiple Ub molecules are assembled.
- ER exit sites
-
Areas of the endoplasmic reticulum (ER) where transport vesicles that contain lipids and proteins made in the ER detach from the ER and move to the Golgi complex.
- Galectins
-
Carbohydrate-binding lectins that recognize intracellular bacteria-containing vesicles when their membrane integrity is compromised.
- SNAREs
-
Proteins that mediate the fusion of vesicles with target membranes. SNARE proteins on the vesicle (v-SNAREs) and on the target membrane (t-SNAREs) combine to form a trans-SNARE complex that provides the force for membrane fusion.
- Hippo kinase
-
A kinase that functions as a central node in the regulation of cell division and controls organ size in flies and mammals as well as the growth of cancer cells.
- High-mobility group box 1 protein (HMGB1)
-
A protein that senses and coordinates the cellular stress response acting as a DNA chaperone, autophagy sustainer and protector from apoptotic cell death. Outside the cell, it functions as a prototypic damage associated molecular pattern molecule (DAMP).
- Unconventional secretion
-
Comprises the translocation across the plasma membrane of cargo without a signal peptide or a transmembrane domain and cargos that reach the plasma membrane by bypassing the Golgi apparatus despite entering the endoplasmic reticulum (ER).
- Exosomes
-
Small extracellular vesicles that contain various molecular constituents and are released directly from the plasma membrane or when multivesicular bodies fuse with the plasma membrane.
- NF-κB (nuclear factor-κB) pathway
-
A transcription factor that controls cytokine production and cell survival and plays a key role in the cellular response to infection. Disturbance of the pathway has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development.
- Leading edge
-
Front edge of a cell that is pushed forward by rapid actin polymerization.
Rights and permissions
About this article
Cite this article
Dikic, I., Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 19, 349–364 (2018). https://doi.org/10.1038/s41580-018-0003-4
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41580-018-0003-4
This article is cited by
-
Exosomes derived from programmed cell death: mechanism and biological significance
Cell Communication and Signaling (2024)
-
Diagnostic and prognostic value of single nucleotide polymorphisms in autophagy-related genes (ATG) among Egyptian patients with breast cancer disease
Egyptian Journal of Medical Human Genetics (2024)
-
The application of nanoparticles-based ferroptosis, pyroptosis and autophagy in cancer immunotherapy
Journal of Nanobiotechnology (2024)
-
Role of ferroptosis and ferroptosis-related long non'coding RNA in breast cancer
Cellular & Molecular Biology Letters (2024)
-
Atg5 deficiency in macrophages protects against kidney fibrosis via the CCR6-CCL20 axis
Cell Communication and Signaling (2024)
