Skip to main content
SpringerLink
Log in

Regulation of autophagy in mammals and its interplay with apoptosis

  • Multi-author Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

A growing number of publications show that apoptosis induction is often associated with increased autophagy indicating the existence of an interplay between these two important cellular events. The simultaneous activation of both phenomena has been detected not only in experimental settings but also in vivo under physiological and pathological conditions. Despite these studies, the reciprocal influence of the two pathways in vivo has still not been completely understood. It is clear that autophagy and apoptosis are strictly interconnected, as highlighted by the finding that the two pathways share key molecular regulators. Many novel aspects of the crosstalk between apoptosis and autophagy have recently emerged showing how complex is this relationship and how critical is for the overall fate of the cell. In this mini-review we will focus on some key experiments trying to decipher as to whether autophagy contributes to apoptosis modulation in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Kroemer G, Levine B (2008) Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 9:1004–1010

    Article  CAS  PubMed  Google Scholar 

  2. Baehrecke EH (2005) Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol 6:505–510

    Article  CAS  PubMed  Google Scholar 

  3. Zakeri Z, Bursch W, Tenniswood M, Lockshin RA (1995) Cell death: programmed, apoptosis, necrosis, or other? Cell Death Differ 2:87–96

    CAS  PubMed  Google Scholar 

  4. Baehrecke EH (2003) Autophagic programmed cell death in Drosophila. Cell Death Differ 10:940–945

    Article  CAS  PubMed  Google Scholar 

  5. Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4:600–606

    CAS  PubMed  Google Scholar 

  6. Bortoluci KR , Medzhitov R (2010) Control of infection by pyroptosis and autophagy: role of TLR and NLR. Cell Mol Life Sci (in press)

  7. Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2:211–216

    Article  CAS  PubMed  Google Scholar 

  8. Deter RL, Baudhuin P, de Duve C (1967) Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J Cell Biol 35:11–16

    Article  Google Scholar 

  9. Suzuki K, Ohsumi Y (2007) Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett 58:2156–2161

    Article  Google Scholar 

  10. Todde V, Veenhuis M, van der Klei IJ (2009) Autophagy: principles and significance in health and disease. Biochim Biophys Acta 1792:3–13

    CAS  PubMed  Google Scholar 

  11. Simonsen A, Stenmark H (2008) Self-eating from an ER-associated cup. J Cell Biol 182:621–622

    Article  CAS  PubMed  Google Scholar 

  12. Massey AC, Zhang C, Cuervo AM (2006) Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 73:205–235

    Article  CAS  PubMed  Google Scholar 

  13. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8:1124–1132

    Article  CAS  PubMed  Google Scholar 

  14. Ullman E, Fan Y, Stawowczyk M, Chen H, Yue Z, Zong W (2008) Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress. Cell Death Differ 15:422–425

    Article  CAS  PubMed  Google Scholar 

  15. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975

    Article  CAS  PubMed  Google Scholar 

  16. Kihara A, Noda T, Ishihara N, Ohsumi Y (2001) Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 152:519–530

    Article  CAS  PubMed  Google Scholar 

  17. Itakura E, Kishi C, Inoue K, Mizushima N (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19:5360–5372

    Article  CAS  PubMed  Google Scholar 

  18. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  CAS  PubMed  Google Scholar 

  19. Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor mechanism. Oncogene 23:2891–2906

    Article  CAS  PubMed  Google Scholar 

  20. Díaz-Troya S, Pérez-Pérez ME, Florencio FJ, Crespo JL (2008) The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 4:851–865

    PubMed  Google Scholar 

  21. Arsham AM, Neufeld TP (2006) Thinking globally and acting locally with TOR. Curr Opin Cell Biol 18:589–599

    Article  CAS  PubMed  Google Scholar 

  22. Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB (2007) The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9:218–224

    Article  CAS  PubMed  Google Scholar 

  23. Chan EY, Longatti A, McKnight NC, Tooze SA (2009) Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol 29:157–171

    Article  CAS  PubMed  Google Scholar 

  24. Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N (2008) FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181:497–510

    Article  CAS  PubMed  Google Scholar 

  25. Matsushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y, Inagaki F (2007) Structure of Atg5.Atg16, a complex essential for autophagy. J Biol Chem 282:6763–6772

    Article  CAS  PubMed  Google Scholar 

  26. Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH, Jung JU (2006) Autophagic and tumor suppressor activity of a novel Beclin 1-binding protein UVRAG. Nat Cell Biol 8:688–699

    Article  CAS  PubMed  Google Scholar 

  27. Sun Q, Fan W, Chen K, Ding X, Chen S, Zhong Q (2008) Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 105:19211–19216

    Article  CAS  PubMed  Google Scholar 

  28. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Corazzari M, Fuoco C, Ucar A, Schwartz P, Gruss P, Piacentini M, Chowdhury K, Cecconi F (2007) Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–1125

    CAS  PubMed  Google Scholar 

  29. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396

    Article  CAS  PubMed  Google Scholar 

  30. Takahashi Y, Meyerkord CL, Wang HG (2009) Bif-1/Endophilin B1: a candidate for crescent driving force in autophagy. Cell Death Differ 16:947–955

    Article  CAS  PubMed  Google Scholar 

  31. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, Kroemer G (2009) Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 16:87–93

    Article  CAS  PubMed  Google Scholar 

  32. Zhang J, Ney PA (2009) Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 16:939–946

    Article  CAS  PubMed  Google Scholar 

  33. Yee KS, Wilkinson S, James J, Ryan KM, Vousden KH (2009) PUMA-and Bax-induced autophagy contributes to apoptosis. Cell Death Differ 16:1135–1145

    Article  CAS  PubMed  Google Scholar 

  34. Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4:600–606

    CAS  PubMed  Google Scholar 

  35. Bialik S, Kimchi A (2006) The death-associated protein kinases: structure, function and beyond. Annu Rev Biochem 75:189–210

    Article  CAS  PubMed  Google Scholar 

  36. Wei Y, Sinha S, Levine B (2008) Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy 4:949–951

    CAS  PubMed  Google Scholar 

  37. Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, Sabanay H, Pinkas-Kramarski R, Kimchi A (2009) DAPk-mediated phosphorylation on the BH3 domain of Beclin-1 promotes dissociation of Beclin-1 from Bcl-XL to induce autophagy. EMBO Rep 10:285–292

    Article  CAS  PubMed  Google Scholar 

  38. Pyo JO, Nah J, Kim HJ, Lee HJ, Heo J, Lee H, Jung YK (2008) Compensatory activation of ERK1/2 in Atg5-deficient mouse embryo fibroblasts suppresses oxidative stress-induced cell death. Autophagy 4:315–321

    CAS  PubMed  Google Scholar 

  39. Salazar M, Carracedo A, Salanueva IJ, Hernández-Tiedra S, Lorente M, Egia A, Vázquez P, Blázquez C, Torres S, García S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, González-Feria L, Iovanna JL, Guzmán M, Boya P, Velasco G (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 119:1359–1372

    Article  CAS  PubMed  Google Scholar 

  40. Gozuacik D, Bialik S, Raveh T, Mitou G, Shohat G, Sabanay H, Mizushima N, Yoshimori T, Kimchi A (2008) DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ 15:1875–1886

    Article  CAS  PubMed  Google Scholar 

  41. Bell BD, Walsh CM (2009) Coordinate regulation of autophagy and apoptosis in T cells by death effectors: FADD or foundation. Autophagy 5:238–240

    Article  CAS  PubMed  Google Scholar 

  42. Betin VM, Lane JD (2009) Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis. J Cell Sci 122:2554–2566

    Article  CAS  PubMed  Google Scholar 

  43. Luo S, Rubinsztein DC (2009) Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ Aug 28 [Epub ahead of print]

  44. Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, Vergne I, Deretic V, Feng P, Akazawa C, Jung JU (2008) Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10:776–787

    Article  CAS  PubMed  Google Scholar 

  45. Crighton D, Wilkinson S, Ryan KM (2007) DRAM links autophagy to p53 and programmed cell death. Autophagy 3:72–74

    CAS  PubMed  Google Scholar 

  46. Yue Z, Jin S, Yang C, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 100:15077–15082

    Article  CAS  PubMed  Google Scholar 

  47. Liang CC, Wang C, Peng X, Gan B, Guan JL (2009) Neural specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J Biol Chem. Nov 24. (Epub ahead of print)

  48. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036

    Article  CAS  PubMed  Google Scholar 

  49. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425–434

    Article  CAS  PubMed  Google Scholar 

  50. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW (2007) A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 204:25–31

    Article  CAS  PubMed  Google Scholar 

  51. Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K (2009) The role of autophagy in the heart. Cell Death Differ 16:31–38

    Article  CAS  PubMed  Google Scholar 

  52. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, Omiya S, Mizote I, Matsumura Y, Asahi M, Nishida K, Hori M, Mizushima N, Otsu K (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624

    Article  CAS  PubMed  Google Scholar 

  53. Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN, Gilpin C, Levine B (2007) Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128:931–946

    Article  CAS  PubMed  Google Scholar 

  54. Lee JS, Li Q, Lee JY, Lee SH, Jeong JH, Lee HR, Chang H, Zhou FC, Gao SJ, Liang C, Jung JU (2009) FLIP-mediated autophagy regulation in cell death control. Nat Cell Biol 11:1355–1362

    Article  CAS  PubMed  Google Scholar 

  55. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M, Criollo A, Morselli E, Zhu C, Harper F, Nannmark U, Samara C, Pinton P, Vicencio JM, Carnuccio R, Moll UM, Madeo F, Paterlini-Brechot P, Rizzuto R, Szabadkai G, Pierron G, Blomgren K, Tavernarakis N, Codogno P, Cecconi F, Kroemer G (2008) Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10:676–687

    Article  CAS  PubMed  Google Scholar 

  56. Green DR, Kroemer G (2009) Cytoplasmic functions of the tumor suppressor p53. Nature 458:1127–1130

    Article  CAS  PubMed  Google Scholar 

  57. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117:326–336

    Article  CAS  PubMed  Google Scholar 

  58. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E (2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 21:1621–1635

    Article  CAS  PubMed  Google Scholar 

  59. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137:1062–1075

    Article  CAS  PubMed  Google Scholar 

  60. Matarrese P, Ciarlo L, Tinari A, Piacentini M, Malorni W (2008) Xeno-cannibalism as an exacerbation of self-cannibalism: a possible fruitful survival strategy for cancer cells. Curr Pharm Des 14:245–252

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Ministry of Health of Italy “Ricerca Corrente” and “Ricerca Finalizzata” to G.M.F. and M.P., EU Marie Curie grant “TRACKS”, AIRC, Banca S. Paolo and Fondazione Telethon to M.P. The support of the EU grant “Apo-Sys” to M.P. is also acknowledged.

Author information

Authors and Affiliations

  1. National Institute for Infectious Diseases IRCCS “Lazzaro Spallanzani”, 00149, Rome, Italy

    Gian Maria Fimia & Mauro Piacentini

  2. Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica 1, 00133, Rome, Italy

    Mauro Piacentini

Authors
  1. Gian Maria Fimia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mauro Piacentini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mauro Piacentini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fimia, G.M., Piacentini, M. Regulation of autophagy in mammals and its interplay with apoptosis. Cell. Mol. Life Sci. 67, 1581–1588 (2010). https://doi.org/10.1007/s00018-010-0284-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0284-z

Keywords

Search

Navigation