Chapter 26 : Autophagy: a Fundamental Cytoplasmic Sanitation Process Operational in All Cell Types Including Macrophages

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Autophagy: a Fundamental Cytoplasmic Sanitation Process Operational in All Cell Types Including Macrophages, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap26-1.gif /docserver/preview/fulltext/10.1128/9781555816650/9781555814014_Chap26-2.gif


Autophagic degradation is a cell-autonomous mechanism for direct elimination of intracellular microbes, but also plays a broader role in innate and adaptive immunity and in general cytoplasmic homeostasis. The process of autophagy plays many functions, including feeding the cells under starvation conditions or upon withdrawal of growth factors. Autophagy plays both housekeeping and immune functions in macrophages and dendritic cells. The phagophore is enlarged by the addition of a new membrane that is of undefined origin but is suspected to come from the endoplasmic reticulum or a combination of sources including Golgi and endosomes. Most cells undergo baseline autophagy, removing protein aggregates and spuriously damaged mitochondria or other organelles, or adjusting the cellular biomass. The classical physiological inducers of autophagy are amino acid starvation or absence of growth factors. Recent studies examining effects on the redistribution of a sole integral membrane Atg protein, Atg9, have implicated ULK1 as the putative mammalian Atg1 ortholog. A classical physiological inducer of autophagy is amino acid starvation, in particular, withdrawal of leucine. In mammalian cells, the role of autophagy has been linked to immunological signals. In mice and humans it is under the control of cytokines and agonists regulating innate and adaptive immunity, such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 13 (IL-13), and CD40L-CD40.

Citation: Deretic V. 2009. Autophagy: a Fundamental Cytoplasmic Sanitation Process Operational in All Cell Types Including Macrophages, p 419-425. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch26
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Execution stages of the autophagic pathway. See text for explanations. Reproduced with permission from .

Citation: Deretic V. 2009. Autophagy: a Fundamental Cytoplasmic Sanitation Process Operational in All Cell Types Including Macrophages, p 419-425. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Core signaling pathways regulating autophagy. Light gray boxes, agonists of autophagy (positive regulators); dark gray boxes, antagonists of autophagy (negative regulators). See text for description and explanations.

Citation: Deretic V. 2009. Autophagy: a Fundamental Cytoplasmic Sanitation Process Operational in All Cell Types Including Macrophages, p 419-425. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Immunologically relevant inputs (dotted boxes) and outputs (solid boxes) of autophagy. See text for details and references. Adapted from .

Citation: Deretic V. 2009. Autophagy: a Fundamental Cytoplasmic Sanitation Process Operational in All Cell Types Including Macrophages, p 419-425. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Andrade, R. M.,, M. Wessendarp,, M. J. Gubbels,, B. Striepen, and, C. S. Subauste. 2006. CD40 induces macrophage anti- Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Invest. 116: 23662377.
2. Anes, E.,, M. P. Kuhnel,, E. Bos,, J. Moniz-Pereira,, A. Habermann, and, G. Griffiths. 2003. Selected lipids activate phagosome actin assembly and maturation resulting in killing of pathogenic mycobacteria. Nat. Cell. Biol. 5: 793802.
3. Arico, S.,, A. Petiot,, C. Bauvy,, P. F. Dubbelhuis,, A. J. Meijer,, P. Codogno, and, E. Ogier-Denis. 2001. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 276: 3524335246.
4. Bekpen, C.,, J. P. Hunn,, C. Rohde,, I. Parvanova,, L. Guethlein,, D. M. Dunn,, E. Glowalla,, M. Leptin, and, J. C. Howard. 2005. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol. 6: R92.
5. Berwick, D. C.,, G. C. Dell,, G. I. Welsh,, K. J. Heesom,, I. Hers,, L. M. Fletcher,, F. T. Cooke, and, J. M. Tavare. 2004. Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles. J. Cell Sci. 117: 59855993.
6. Birmingham, C. L.,, A. C. Smith,, M. A. Bakowski,, T. Yoshimori, and, J. H. Brumell. 2006. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J. Biol. Chem. 281: 1137411383.
7. Bjorkoy, G.,, T. Lamark,, A. Brech,, H. Outzen,, M. Perander,, A. Overvatn,, H. Stenmark, and, T. Johansen. 2005. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171: 603614.
8. Byfield, M. P.,, J. T. Murray, and, J. M. Backer. 2005. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J. Biol. Chem. 280: 3307633082.
9. Checroun, C.,, T. D. Wehrly,, E. R. Fischer,, S. F. Hayes, and, J. Celli. 2006. Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment after cytoplasmic replication. Proc. Natl. Acad. Sci. USA 103: 1457814583.
10. Deretic, V. 2005. Autophagy in innate and adaptive immunity. Trends Immunol. 26: 523528.
11. Deretic, V. 2006. Autophagy as an immune defense mechanism. Curr. Opin. Immunol. 18: 375382.
12. Djavaheri-Mergny, M.,, M. Amelotti,, J. Mathieu,, F. Besancon,, C. Bauvy,, S. Souquere,, G. Pierron, and, P. Codogno. 2006. NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy. J. Biol. Chem. 281: 3037330382.
13. Dove, S. K.,, R. C. Piper,, R. K. McEwen,, J. W. Yu,, M. C. King,, D. C. Hughes,, J. Thuring,, A. B. Holmes,, F. T. Cooke,, R. H. Michell,, P. J. Parker, and, M. A. Lemmon. 2004. Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J. 23: 19221933.
14. Dunn, W. A., Jr. 1990. Studies on the mechanisms of autophagy: formation of the autophagic vacuole. J. Cell Biol. 110: 19231933.
15. Furuya, T.,, J. Yu,, M. Byfield,, S. Pattingre, and, B. Levine. 2005. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 1: 4652.
16. Gutierrez, M. G.,, S. S. Master,, S. B. Singh,, G. A. Taylor,, M. I. Colombo, and, V. Deretic. 2004. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119: 753766.
17. Hampe, J.,, A. Franke,, P. Rosenstiel,, A. Till,, M. Teuber,, K. Huse,, M. Albrecht,, G. Mayr,, F. M. De La Vega,, J. Briggs,, S. Günther,, N. J. Prescott,, C. M. Onnie,, R. Häsler,, B. Sipos,, U. R. Fölsch,, T. Lengauer,, M. Platzer,, C. G. Mathew,, M. Krawczak, and, S. Schreiber. 2007. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39: 207211.
18. Høyer-Hansen, M.,, L. Bastholm,, I. S. Mathiasen,, F. Elling, and, M. Jäättelä. 2005. Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ. 12: 12971309.
19. Høyer-Hansen, M.,, L. Bastholm,, P. Szyniarowski,, M. Campanella,, G. Szabadkai,, T. Farkas,, K. Bianchi,, N. Fehrenbacher,, F. Elling,, R. Rizzuto,, I. S. Mathiasen, and, M. Jäättelä. 2007. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol. Cell 25: 193205.
20. Hsu, Y. C.,, J. J. Chern,, Y. Cai,, M. Liu, and, K. W. Choi. 2007. Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature 445: 785788.
21. Inbal, B.,, S. Bialik,, I. Sabanay,, G. Shani, and, A. Kimchi. 2002. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J. Cell Biol. 157: 455468.
22. Klionsky, D. J. 2005. The molecular machinery of autophagy: unanswered questions. J. Cell. Sci. 118: 718.
23. Krick, R.,, J. Tolstrup,, A. Appelles,, S. Henke, and, M. Thumm. 2006. The relevance of the phosphatidylinositolphosphate-binding motif FRRGT of Atg18 and Atg21 for the Cvt pathway and autophagy. FEBS Lett. 580: 46324638.
24. Lavieu, G.,, F. Scarlatti,, G. Sala,, S. Carpentier,, T. Levade,, R. Ghidoni,, J. Botti, and, P. Codogno. 2006. Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation. J. Biol. Chem. 281: 85188527.
25. Lee, H. K.,, J. M. Lund,, B. Ramanathan,, N. Mizushima, and, A. Iwasaki. 2007. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315: 13981401.
26. Li, C.,, E. Capan,, Y. Zhao,, J. Zhao,, D. Stolz,, S. C. Watkins,, S. Jin, and, B. Lu. 2006. Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death. J. Immunol. 177: 51635168.
27. Liang, C.,, P. Feng,, B. Ku,, I. Dotan,, D. Canaani,, B. H. Oh, and, J. U. Jung. 2006. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat. Cell Biol. 8: 688699.
28. Liang, X. H.,, S. Jackson,, M. Seaman,, K. Brown,, B. Kempkes,, H. Hibshoosh, and, B. Levine. 1999. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402: 672676.
29. Ling, Y. M.,, M. H. Shaw,, C. Ayala,, I. Coppens,, G. A. Taylor,, D. J. Ferguson, and, G. S. Yap. 2006. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J. Exp. Med. 203: 20632071.
30. Liu, P. T.,, S. Stenger,, H. Li,, L. Wenzel,, B. H. Tan,, S. R. Krutzik,, M. T. Ochoa,, J. Schauber,, K. Wu,, C. Meinken,, D. L. Kamen,, M. Wagner,, R. Bals,, A. Steinmeyer,, U. Zügel,, R. L. Gallo,, D. Eisenberg,, M. Hewison,, B. W. Hollis,, J. S. Adams,, B. R. Bloom, and, R. L. Modlin. 2006. Tolllike receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 17701773.
31. Lum, J. J.,, D. E. Bauer,, M. Kong,, M. H. Harris,, C. Li,, T. Lindsten, and, C. B. Thompson. 2005. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120: 237248.
32. MacMicking, J. D.,, G. A. Taylor, and, J. D. McKinney. 2003. Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science 302: 654659.
33. Maiuri, M. C.,, G. Le Toumelin,, A. Criollo,, J. C. Rain,, F. Gautier,, P. Juin,, E. Tasdemir,, G. Pierron,, K. Troulinaki,, N. Tavernarakis,, J. A. Hickman,, O. Geneste, and, G. Kroemer. 2007. Functional and physical interaction between BclX(L) and a BH3-like domain in Beclin-1. EMBO J. 26: 25272539.
34. Meley, D.,, C. Bauvy,, J. H. Houben-Weerts,, P. F. Dubbelhuis,, M. T. Helmond,, P. Codogno, and, A. J. Meijer. 2006. AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem. 281: 3487034879.
35. Nakagawa, I.,, A. Amano,, N. Mizushima,, A. Yamamoto,, H. Yamaguchi,, T. Kamimoto,, A. Nara,, J. Funao,, M. Nakata,, K. Tsuda,, S. Hamada, and, T. Yoshimori. 2004. Autophagy defends cells against invading group A Streptococcus. Science 306: 10371040.
36. Nobukuni, T.,, M. Joaquin,, M. Roccio,, S. G. Dann,, S. Y. Kim,, P. Gulati,, M. P. Byfield,, J. M. Backer,, F. Natt,, J. L. Bos,, F. J. Zwartkruis, and, G. Thomas. 2005. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl. Acad. Sci. USA 102: 1423814243.
37. Obara, K.,, T. Sekito, and, Y. Ohsumi. 2006. Assortment of phosphatidylinositol 3-kinase complexes—Atg14p directs association of complex I to the preautophagosomal structure in Saccharomyces cerevisiae. Mol. Biol. Cell. 17: 15271539.
38. Ogawa, M.,, T. Yoshimori,, T. Suzuki,, H. Sagara,, N. Mizushima, and, C. Sasakawa. 2005. Escape of intracellular Shigella from autophagy. Science 307: 727731.
39. Orvedahl, A.,, D. Alexander,, Z. Tallóczy,, Q. Sun,, Y. Wei,, W. Zhang,, D. Burns,, D. Leib, and, B. Levine. 2007. HSV-1 ICP34. 5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1: 2335.
40. Paludan, C.,, D. Schmid,, M. Landthaler,, M. Vockerodt,, D. Kube,, T. Tuschl, and, C. Munz. 2005. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307: 593596.
41. Pattingre, S.,, A. Tassa,, X. Qu,, R. Garuti,, X. H. Liang,, N. Mizushima,, M. Packer,, M. D. Schneider, and, B. Levine. 2005. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927939.
42. Petiot, A.,, E. Ogier-Denis,, E. F. Blommaart,, A. J. Meijer, and, P. Codogno. 2000. Distinct classes of phosphatidylinositol 3’-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J. Biol. Chem. 275: 992998.
43. Proikas-Cezanne, T.,, S. Waddell,, A. Gaugel,, T. Frickey,, A. Lupas, and, A. Nordheim. 2004. WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvationinduced autophagy. Oncogene 23: 93149325.
44. Pua, H. H.,, I. Dzhagalov,, M. Chuck,, N. Mizushima, and, Y. W. He. 2007. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204: 2531.
45. Py, B. F.,, M. M. Lipinski, and, J. Yuan. 2007. Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3: 117125.
46. Pyo, J. O.,, M. H. Jang,, Y. K. Kwon,, H. J. Lee,, J. I. Jun,, H. N. Woo,, D. H. Cho,, B. Choi,, H. Lee,, J. H. Kim,, N. Mizushima,, Y. Oshumi, and, Y. K. Jung. 2005. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J. Biol. Chem. 280: 2072220729.
47. Reggiori, F.,, T. Shintani,, U. Nair, and, D. J. Klionsky. 2005. Atg9 cycles between mitochondria and the preautophagosomal structure in yeasts. Autophagy 1: 101109.
48. Reggiori, F.,, K. A. Tucker,, P. E. Stromhaug, and, D. J. Klionsky. 2004. The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev. Cell. 6: 7990.
49. Scarlatti, F.,, C. Bauvy,, A. Ventruti,, G. Sala,, F. Cluzeaud,, A. Vandewalle,, R. Ghidoni, and, P. Codogno. 2004. Ceramidemediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J. Biol. Chem. 279: 1838418391.
50. Schmid, D.,, M. Pypaert, and, C. Munz. 2007. Antigenloading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26: 7992.
51. Scott, R. C.,, G. Juhasz, and, T. P. Neufeld. 2007. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr. Biol. 17: 111.
52. Singh, S. B.,, A. S. Davis,, G. A. Taylor, and, V. Deretic. 2006. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313: 14381441.
53. Sofer, A.,, K. Lei,, C. M. Johannessen, and, L. W. Ellisen. 2005. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol. Cell. Biol. 25: 58345845.
54. Taylor, G. A.,, C. G. Feng, and, A. Sher. 2004. p47 GTPases: regulators of immunity to intracellular pathogens. Nat. Rev. Immunol. 4: 100109.
55. Thompson, C. R.,, S. S. Iyer,, N. Melrose,, R. VanOosten,, K. Johnson,, S. M. Pitson,, L. M. Obeid, and, D. J. Kusner. 2005. Sphingosine kinase 1 (SK1) is recruited to nascent phagosomes in human macrophages: inhibition of SK1 translocation by Mycobacterium tuberculosis. J. Immunol. 174: 35513561.
56. Wullschleger, S.,, R. Loewith, and, M. N. Hall. 2006. TOR signaling in growth and metabolism. Cell 124: 471484.
57. Yamamoto, A.,, R. Masaki, and, Y. Tashiro. 1990. Characterization of the isolation membranes and the limiting membranes of autophagosomes in rat hepatocytes by lectin cytochemistry. J. Histochem. Cytochem. 38: 573580.
58. Young, A. R.,, E. Y. Chan,, X. W. Hu,, R. Kochl,, S. G. Crawshaw,, S. High,, D. W. Hailey,, J. Lippincott-Schwartz, and, S. A. Tooze. 2006. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119: 38883900.
59. Zeng, X.,, J. H. Overmeyer, and, W. A. Maltese. 2006. Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J. Cell Sci. 119: 259270.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error