Amino Acids

, Volume 47, Issue 10, pp 2101–2112 | Cite as

Autophagy response: manipulating the mTOR-controlled machinery by amino acids and pathogens

  • Claudio Marcelo Fader
  • Milton Osmar Aguilera
  • María Isabel Colombo
Invited Review
First Online:
Received:
Accepted:

Abstract

Macroautophagy is a self-degradative process that normally maintains cellular homeostasis via a lysosomal pathway. It is induced by different stress signals, including nutrients and growth factors’ restriction as well as pathogen invasions. These stimuli are modulated by the serine/threonine protein kinase mammalian target of rapamycin (mTOR) which control not only autophagy but also protein translation and gene expression. This review focuses on the important role of mTOR as a master regulator of cell growth and the autophagy pathway. Here, we have discussed the role of intracellular amino acid availability and intracellular pH in the redistribution of autophagic structures, which may contribute to mammalian target of rapamycin complex 1 (mTORC1) activity regulation. We have also discussed that mTORC1 complex and components of the autophagy machinery are localized at the lysosomal surface, representing a fascinating mechanism to control the metabolism, cellular clearance and also to restrain invading intracellular pathogens.

Keywords

Autophagy LC3 Pathogens Amino acids mTOR 
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Notes

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. Aguilera, Milton. O, Walter. B, María. I. C (2012) The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy. Autophagy (Novemb): 1–14. Retrieved from http://www.landesbioscience.com/journals/autophagy/2012AUTO0073R1.pdf
  2. Backer JM (2008) The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J 410(1):1–17. doi: 10.1042/BJ20071427 CrossRefPubMedGoogle Scholar
  3. Baird Thomas D, Wek Ronald C (2012) Eukaryotic initiation factor 2 phosphorylation and translational control in metabolism. Adv Nutr(Bethesda, Md.) 3(3):307–321. doi: 10.3945/an.112.002113 CrossRefGoogle Scholar
  4. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM (2012) Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150(6):1196–1208. doi: 10.1016/j.cell.2012.07.032 PubMedCentralCrossRefPubMedGoogle Scholar
  5. Betz C, Hall MN (2013) Where is mTOR and what is it doing there? J Cell Biol 203(4):563–574. doi: 10.1083/jcb.201306041 PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bonfils G, Jaquenoud M, Bontron S, Ostrowicz C, Ungermann C, De Virgilio C (2012) Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol Cell 46(1):105–110. doi: 10.1016/j.molcel.2012.02.009 CrossRefPubMedGoogle Scholar
  7. Boya P, Reggiori F, Codogno P (2013) Emerging regulation and functions of autophagy. Nat Cell Biol 15(7):713–720. doi: 10.1038/ncb2788 CrossRefPubMedGoogle Scholar
  8. Bruckert WM, Price CT, Abu Kwaik Y (2014) Rapid nutritional remodeling of the host cell upon attachment of Legionella pneumophila. Infect and Immun 82(1):72–82. doi: 10.1128/IAI.01079-13 CrossRefGoogle Scholar
  9. Buerger C, DeVries B, Stambolic V (2006) Localization of Rheb to the endomembrane is critical for its signaling function. Biochem Biophys Res Commun 344(3):869–880. doi: 10.1016/j.bbrc.2006.03.220 CrossRefPubMedGoogle Scholar
  10. Castilho BA, Shanmugam R, Silva RC, Ramesh R, Himme BM, Sattlegger E (2014) Keeping the eIF2 alpha kinase Gcn2 in check. Biochim Biophys Acta. doi: 10.1016/j.bbamcr.2014.04.006 PubMedGoogle Scholar
  11. Chang Y-Y, Juhász G, Goraksha-Hicks P, Arsham AM, Mallin DR, Muller LK, Neufeld TP (2009) Nutrient-dependent regulation of autophagy through the target of rapamycin pathway. Biochem Soc Trans 37(Pt 1):232–236. doi: 10.1042/BST0370232 CrossRefPubMedGoogle Scholar
  12. Cosma CL, Humbert O, Sherman DR, Ramakrishnan L (2008) Trafficking of superinfecting Mycobacterium organisms into established granulomas occurs in mammals and is independent of the Erp and ESX-1 mycobacterial virulence loci. J Infect Dis 198(12):1851–1855. doi: 10.1086/593175 PubMedCentralCrossRefPubMedGoogle Scholar
  13. Dales. S, Eggers. H. J, Tamm. I, Palade. G. E (1965) Electron microscopic study of the formation of poliovirus. Virology 26: 379–89 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14319710
  14. Deretic V, Levine B (2009) Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5(6):527–549. doi: 10.1016/j.chom.2009.05.016 PubMedCentralCrossRefPubMedGoogle Scholar
  15. Efeyan A, Zoncu R, Sabatini DM (2012) Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med 18(9):524–533. doi: 10.1016/j.molmed.2012.05.007 PubMedCentralCrossRefPubMedGoogle Scholar
  16. Fader CM, Aguilera MO, Colombo MI (2012) ATP is released from autophagic vesicles to the extracellular space in a VAMP7-dependent manner. Autophagy 8(12):1741–1756. doi: 10.4161/auto.21858 PubMedCentralCrossRefPubMedGoogle Scholar
  17. Flinn RJ, Yan Y, Goswami S, Parker PJ, Backer JM (2010) The late endosome is essential for mTORC1 signaling. Mol Biol Cell 21(5):833–841. doi: 10.1091/mbc.E09-09-0756 PubMedCentralCrossRefPubMedGoogle Scholar
  18. Fonseca BD, Smith EM, Lee VH-Y, MacKintosh C, Proud CG (2007) PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J Biol Chem 282(34):24514–24524. doi: 10.1074/jbc.M704406200 CrossRefPubMedGoogle Scholar
  19. Ganley IG, Lam DH, Wang J, Ding X, Chen S, Jiang X (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284(18):12297–12305. doi: 10.1074/jbc.M900573200 PubMedCentralCrossRefPubMedGoogle Scholar
  20. Gao M, Kaiser CA (2006) A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nat Cell Biol 8(7):657–667. doi: 10.1038/ncb1419 CrossRefPubMedGoogle Scholar
  21. Gao L-Y, Guo S, McLaughlin B, Morisaki H, Engel JN, Brown EJ (2004) A mycobacterial virulence gene cluster extending RD1 is required for cytolysis, bacterial spreading and ESAT-6 secretion. Mol Microbiol 53(6):1677–1693. doi: 10.1111/j.1365-2958.2004.04261.x CrossRefPubMedGoogle Scholar
  22. Goberdhan. D. C. I (2010) Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target? Current Opinion in Investigational Drugs (London, England: 2000) 11(12): 1360–7. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3044466&tool=pmcentrez&rendertype=abstract
  23. Goberdhan DCI, Meredith D, Boyd CAR, Wilson C (2005) PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids. Development 132(10):2365–2375. doi: 10.1242/dev.01821 CrossRefPubMedGoogle Scholar
  24. Gordon BS, Kazi A, Coleman CS, Dennis MD, Chau V, Jefferson LS, Kimball SR (2014) RhoA modulates signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in mammalian cells. Cel Signal 26(3):461–467. doi: 10.1016/j.cellsig.2013.11.035 CrossRefGoogle Scholar
  25. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119(6):753–766. doi: 10.1016/j.cell.2004.11.038 CrossRefPubMedGoogle Scholar
  26. Gutierrez MG, Vázquez CL, Munafó DB, Zoppino FCM, Berón W, Rabinovitch M, Colombo MI (2005) Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell Microbiol 7(7):981–993. doi: 10.1111/j.1462-5822.2005.00527.x CrossRefPubMedGoogle Scholar
  27. Hamasaki M, Yoshimori T (2010) Where do they come from? Insights into autophagosome formation. FEBS Letters 584(7):1296–1301. doi: 10.1016/j.febslet.2010.02.061 CrossRefPubMedGoogle Scholar
  28. Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Kim S (2012) Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149(2):410–424. doi: 10.1016/j.cell.2012.02.044 CrossRefPubMedGoogle Scholar
  29. Hara. T, Mizushima. N (2009) Role of ULK-FIP200 complex in mammalian autophagy. (January) 85–87. doi:10.1083/jcb.200712064.www.landesbioscience.com
  30. Heaton NS, Randall G (2010) Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe 8(5):422–432. doi: 10.1016/j.chom.2010.10.006 PubMedCentralCrossRefPubMedGoogle Scholar
  31. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Mizushima N (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20(7):1981–1991PubMedCentralCrossRefPubMedGoogle Scholar
  32. Itakura. E, Mizushima. N (2010) Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6(6): 764–76. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3321844&tool=pmcentrez&rendertype=abstract
  33. 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(12):5360–5372. doi: 10.1091/mbc.E08-01-0080 PubMedCentralCrossRefPubMedGoogle Scholar
  34. Ivanov SS, Roy CR (2013) Pathogen signatures activate a ubiquitination pathway that modulates the function of the metabolic checkpoint kinase mTOR. Nat Immunol 14(12):1219–1228. doi: 10.1038/ni.2740 CrossRefPubMedGoogle Scholar
  35. Jackson WT, Giddings TH, Taylor MP, Mulinyawe S, Rabinovitch M, Kopito RR, Kirkegaard K (2005) Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol 3(5):e156. doi: 10.1371/journal.pbio.0030156 PubMedCentralCrossRefPubMedGoogle Scholar
  36. Jaramillo M, Gomez MA, Larsson O, Shio MT, Topisirovic I, Contreras I, Sonenberg N (2011) Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection. Cell Host Microbe 9(4):331–341. doi: 10.1016/j.chom.2011.03.008 CrossRefPubMedGoogle Scholar
  37. Jung Chang Hwa, Jun Chang Bong, Ro Seung-Hyun, Kim Young-Mi, Otto Neil Michael, Cao Jing, Kundu Mondira, Kim Do-Hyung (2009) ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20(7):1992–2003. doi: 10.1091/mbc.E08-12-1249 PubMedCentralCrossRefPubMedGoogle Scholar
  38. Jung CH, Seo M, Otto NM, Kim D-H (2011) ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7(10):1212–1221. doi: 10.4161/auto.7.10.16660 PubMedCentralCrossRefPubMedGoogle Scholar
  39. Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Thomas G (2010) Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 11(5):390–401. doi: 10.1016/j.cmet.2010.03.014 PubMedCentralCrossRefPubMedGoogle Scholar
  40. Kao Tseng-Ting Tu, Hung-Chi Chang Wen-Ni, Bing-Hung Chen, Ya-Yuang Shi, Chang Tsung-Chain Fu, Tzu-Fun, (2010) Grape seed extract inhibits the growth and pathogenicity of Staphylococcus aureus by interfering with dihydrofolate reductase activity and folate-mediated one-carbon metabolism. Internatl J Food Microbiol 141(1–2):17–27. doi: 10.1016/j.ijfoodmicro.2010.04.025
  41. Karanasios E, Stapleton E, Manifava M, Kaizuka T, Mizushima N, Walker SA, Ktistakis NT (2013) Dynamic association of the ULK1 complex with omegasomes during autophagy induction. J Cell Sci 126(Pt 22):5224–5238. doi: 10.1242/jcs.132415 CrossRefPubMedGoogle Scholar
  42. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan K-L (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10(8):935–945. doi: 10.1038/ncb1753 PubMedCentralCrossRefPubMedGoogle Scholar
  43. Kim J, Kundu M, Viollet B, Guan K-L (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. doi: 10.1038/ncb2152 PubMedCentralCrossRefPubMedGoogle Scholar
  44. Kloft N, Neukirch C, Bobkiewicz W, Veerachato G, Busch T, Von Hoven G, Husmann M (2010) Pro-autophagic signal induction by bacterial pore-forming toxins. Med Microbiol Immun 199(4):299–309. doi: 10.1007/s00430-010-0163-0 CrossRefGoogle Scholar
  45. Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA, Imarisio S, Rubinsztein DC (2011) Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 13(4):453–460. doi: 10.1038/ncb2204 PubMedCentralCrossRefPubMedGoogle Scholar
  46. Lerena MC, Colombo MI (2011) Mycobacterium marinum induces a marked LC3 recruitment to its containing phagosome that depends on a functional ESX-1 secretion system. Cell Microbiol 13(6):814–835. doi: 10.1111/j.1462-5822.2011.01581.x CrossRefPubMedGoogle Scholar
  47. Lewis KN, Liao R, Guinn KM, Hickey MJ, Smith S, Behr MA, Sherman DR (2003) Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette–Guérin attenuation. J Infect Dis 187(1):117–123. doi: 10.1086/345862 PubMedCentralCrossRefPubMedGoogle Scholar
  48. Longatti A, Tooze SA (2009) Vesicular trafficking and autophagosome formation. Cell Death Differ 16(7):956–965. doi: 10.1038/cdd.2009.39 CrossRefPubMedGoogle Scholar
  49. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274. doi: 10.1016/j.cell.2007.06.009 PubMedCentralCrossRefPubMedGoogle Scholar
  50. Martina JA, Puertollano R (2013) Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J Cell Biol 200(4):475–491. doi: 10.1083/jcb.201209135 PubMedCentralCrossRefPubMedGoogle Scholar
  51. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Yoshimori T (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11(4):385–396. doi: 10.1038/ncb1846 CrossRefPubMedGoogle Scholar
  52. Mehrpour M, Esclatine A, Beau I, Codogno P (2010) Autophagy in health and disease. 1. Regulation and significance of autophagy: an overview. Am J Physiol Cell Physiol 298(4):C776–C785. doi: 10.1152/ajpcell.00507.2009 CrossRefPubMedGoogle Scholar
  53. Mestre. M. B, Fader. C. M, Sola. C. Colombo. M. I (2010) Alpha-hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus-infected cells. Autophagy 6(1): 110–25. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20110774
  54. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132. doi: 10.1146/annurev-cellbio-092910-154005 CrossRefPubMedGoogle Scholar
  55. Moreau K, Lacas-Gervais S, Fujita N, Sebbane F, Yoshimori T, Simonet M, Lafont F (2010) Autophagosomes can support Yersinia pseudotuberculosis replication in macrophages. Cell Microbiol 12(8):1108–1123. doi: 10.1111/j.1462-5822.2010.01456.x CrossRefPubMedGoogle Scholar
  56. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Yoshimori T (2004) Autophagy defends cells against invading group A Streptococcus. Sci (New York, N.Y.) 306(5698):1037–1040. doi: 10.1126/science.1103966 CrossRefGoogle Scholar
  57. Nakashima K, Ishida A, Yamazaki M, Abe H (2005) Leucine suppresses myofibrillar proteolysis by down-regulating ubiquitin–proteasome pathway in chick skeletal muscles. Biochem Biophys Res Commun 336(2):660–666. doi: 10.1016/j.bbrc.2005.08.138 CrossRefPubMedGoogle Scholar
  58. Narita M, Young ARJ, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, Narita M (2011) Spatial coupling of mTOR and autophagy augments secretory phenotypes. Sci (New York, N.Y.) 332(6032):966–970. doi: 10.1126/science.1205407 CrossRefGoogle Scholar
  59. Niu H, Yamaguchi M, Rikihisa Y (2008) Subversion of cellular autophagy by Anaplasma phagocytophilum. Cell Microbiol 10(3):593–605. doi: 10.1111/j.1462-5822.2007.01068.x CrossRefPubMedGoogle Scholar
  60. Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Yonezawa K (2007) The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem 282(28):20329–20339. doi: 10.1074/jbc.M702636200 PubMedCentralCrossRefPubMedGoogle Scholar
  61. Paetzold S, Lourido S, Raupach B, Zychlinsky A (2007) Shigella flexneri phagosomal escape is independent of invasion. Infect Immun 75(10):4826–4830. doi: 10.1128/IAI.00454-07 PubMedCentralCrossRefPubMedGoogle Scholar
  62. Powell JD, Pollizzi KN, Heikamp EB, Horton MR (2012) Regulation of immune responses by mTOR. Annu Rev Immunol 30:39–68. doi: 10.1146/annurev-immunol-020711-075024 PubMedCentralCrossRefPubMedGoogle Scholar
  63. Pujol C, Klein KA, Romanov GA, Palmer LE, Cirota C, Zhao Z, Bliska JB (2009) Yersinia pestis can reside in autophagosomes and avoid xenophagy in murine macrophages by preventing vacuole acidification. Infect Immun 77(6):2251–2261. doi: 10.1128/IAI.00068-09 PubMedCentralCrossRefPubMedGoogle Scholar
  64. Pym. A. S, Brodin. P, Brosch. R, Huerre. M, Cole. S. T (2002) Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. Mol Microbiol 46(3): 709–17 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12410828
  65. Randow F (2011) How cells deploy ubiquitin and autophagy to defend their cytosol from bacterial invasion. Autophagy 7(3):304–309. doi: 10.4161/auto.7.3.14539 CrossRefPubMedGoogle Scholar
  66. Rohde K, Yates RM, Purdy GE, Russell DG (2007) Mycobacterium tuberculosis and the environment within the phagosome. Immunol Rev 219:37–54. doi: 10.1111/j.1600-065X.2007.00547.x CrossRefPubMedGoogle Scholar
  67. Romano. P. S, Arboit. M. A, Vázquez. C. L, Colombo. M. I (2009) The autophagic pathway is a key component in the lysosomal dependent entry of Trypanosoma cruzi into the host cell. Autophagy 5(1): 6–18 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19115481
  68. Romano PS, Cueto JA, Casassa AF, Vanrell MC, Gottlieb RA, Colombo MI (2012) Molecular and cellular mechanisms involved in the Trypanosoma cruzi/host cell interplay. IUBMB Life 64(5):387–396. doi: 10.1002/iub.1019 PubMedCentralCrossRefPubMedGoogle Scholar
  69. Russell RC, Tian Y, Yuan H, Park HW, Chang Y-Y, Kim J, Guan K-L (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15(7):741–750. doi: 10.1038/ncb2757 CrossRefPubMedGoogle Scholar
  70. Russell RC, Yuan H-X, Guan K-L (2014) Autophagy regulation by nutrient signaling. Cell Res 24(1):42–57. doi: 10.1038/cr.2013.166 PubMedCentralCrossRefPubMedGoogle Scholar
  71. Saito K, Araki Y, Kontani K, Nishina H, Katada T (2005) Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem 137(3):423–430. doi: 10.1093/jb/mvi046 CrossRefPubMedGoogle Scholar
  72. Salminen A, Kaarniranta K, Kauppinen A (2013) Beclin 1 interactome controls the crosstalk between apoptosis, autophagy and inflammasome activation: impact on the aging process. N.A Res Reviews 12(2):520–534. doi: 10.1016/j.arr.2012.11.004 CrossRefGoogle Scholar
  73. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25(6):903–915. doi: 10.1016/j.molcel.2007.03.003 CrossRefPubMedGoogle Scholar
  74. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Sci (New York, N.Y.) 320(5882):1496–1501. doi: 10.1126/science.1157535 CrossRefGoogle Scholar
  75. Sancak Y, Bar-Peled L, Zoncu R, Markhard A (2010a) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141(2):290–303. doi: 10.1016/j.cell.2010.02.024.Ragulator-Rag PubMedCentralCrossRefPubMedGoogle Scholar
  76. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010b) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141(2):290–303. doi: 10.1016/j.cell.2010.02.024 PubMedCentralCrossRefPubMedGoogle Scholar
  77. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Ballabio A (2009) A gene network regulating lysosomal biogenesis and function. Sci (New York, N.Y.) 325(5939):473–477. doi: 10.1126/science.1174447 Google Scholar
  78. Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5(6):566–571. doi: 10.1038/ncb996 CrossRefPubMedGoogle Scholar
  79. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26(7):1749–1760. doi: 10.1038/sj.emboj.7601623 PubMedCentralCrossRefPubMedGoogle Scholar
  80. Schnaith A, Kashkar H, Leggio SA, Addicks K, Krönke M, Krut O (2007) Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death. J Biol Chem 282(4):2695–2706. doi: 10.1074/jbc.M609784200 CrossRefPubMedGoogle Scholar
  81. Sekiguchi T, Hirose E, Nakashima N, Ii M, Nishimoto T (2001) Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem 276(10):7246–7257. doi: 10.1074/jbc.M004389200 CrossRefPubMedGoogle Scholar
  82. Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG (2005) The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 280(19):18717–18727. doi: 10.1074/jbc.M414499200 CrossRefPubMedGoogle Scholar
  83. Smith J, Manoranjan J, Pan M, Bohsali A, Xu J, Liu J, Gao L-Y (2008) Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infect Immun 76(12):5478–5487. doi: 10.1128/IAI.00614-08 PubMedCentralCrossRefPubMedGoogle Scholar
  84. Steele S, Brunton J, Ziehr B, Taft-Benz S, Moorman N, Kawula T (2013) Francisella tularensis harvests nutrients derived via ATG5-independent autophagy to support intracellular growth. PLoS Pathog 9(8):e1003562. doi: 10.1371/journal.ppat.1003562 PubMedCentralCrossRefPubMedGoogle Scholar
  85. Steele-Mortimer O (2008) The Salmonella-containing vacuole: moving with the times. Curr Opin Microbiol 11(1):38–45. doi: 10.1016/j.mib.2008.01.002 PubMedCentralCrossRefPubMedGoogle Scholar
  86. Stocker H, Radimerski T, Schindelholz B, Wittwer F, Belawat P, Daram P, Hafen E (2003) Rheb is an essential regulator of S6 K in controlling cell growth in Drosophila. Nat Cell Biol 5(6):559–565. doi: 10.1038/ncb995 CrossRefPubMedGoogle Scholar
  87. 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(49):19211–19216. doi: 10.1073/pnas.0810452105 PubMedCentralCrossRefPubMedGoogle Scholar
  88. Suryawan. A, Davis. T. A (2011) Regulation of protein synthesis by amino acids in muscle of neonates. Frontiers Biosci (Landmark Edition), 16, 1445–60. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3139365&tool=pmcentrez&rendertype=abstract
  89. Suzuki K, Kubota Y, Sekito T, Ohsumi Y (2007) Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells Devoted Mol Cell Mech 12(2):209–218. doi: 10.1111/j.1365-2443.2007.01050.x CrossRefGoogle Scholar
  90. Tallóczy Z, Jiang W, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, Levine B (2002) Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci USA 99(1):190–195. doi: 10.1073/pnas.012485299 PubMedCentralCrossRefPubMedGoogle Scholar
  91. Tang D, Kang R, Livesey KM, Cheh C-W, Farkas A, Loughran P, Lotze MT (2010) Endogenous HMGB1 regulates autophagy. J Cell Biol 190(5):881–892. doi: 10.1083/jcb.200911078 PubMedCentralCrossRefPubMedGoogle Scholar
  92. Tang H-W, Liao H-M, Peng W-H, Lin H-R, Chen C-H, Chen G-C (2013) Atg9 interacts with dTRAF2/TRAF6 to regulate oxidative stress-induced JNK activation and autophagy induction. Dev Cell 27(5):489–503. doi: 10.1016/j.devcel.2013.10.017 CrossRefPubMedGoogle Scholar
  93. Tattoli I, Sorbara MT, Vuckovic D, Ling A, Soares F, Carneiro LAM, Girardin SE (2012) Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11(6):563–575. doi: 10.1016/j.chom.2012.04.012 CrossRefPubMedGoogle Scholar
  94. Thurston TLM, Ryzhakov G, Bloor S, von Muhlinen N, Randow F (2009) The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol 10(11):1215–1221. doi: 10.1038/ni.1800 CrossRefPubMedGoogle Scholar
  95. Valbuena N, Rozalén AE, Moreno S (2012) Fission yeast TORC1 prevents eIF2α phosphorylation in response to nitrogen and amino acids via Gcn2 kinase. J Cell Sci 125(Pt 24):5955–5959. doi: 10.1242/jcs.105395 CrossRefPubMedGoogle Scholar
  96. Vance RE (2010) Immunology taught by bacteria. J Clin Immunol 30(4):507–511. doi: 10.1007/s10875-010-9389-2 PubMedCentralCrossRefPubMedGoogle Scholar
  97. Vander Haar E, Lee S-I, Bandhakavi S, Griffin TJ, Kim D-H (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9(3):316–323. doi: 10.1038/ncb1547 CrossRefPubMedGoogle Scholar
  98. Vázquez CL, Colombo MI (2010) Coxiella burnetii modulates Beclin 1 and Bcl-2, preventing host cell apoptosis to generate a persistent bacterial infection. Cell Death Differ 17(3):421–438. doi: 10.1038/cdd.2009.129 CrossRefPubMedGoogle Scholar
  99. Von Hoven G, Kloft N, Neukirch C, Ebinger S, Bobkiewicz W, Weis S, Husmann M (2012) Modulation of translation and induction of autophagy by bacterial exoproducts. Med Microbiol Immun 201(4):409–418. doi: 10.1007/s00430-012-0271-0 CrossRefGoogle Scholar
  100. Weidberg H, Shvets E, Elazar Z (2011) Biogenesis Cargo Sel Autophagosomes. doi: 10.1146/annurev-biochem-052709 Google Scholar
  101. Wu S-B, Wu Y-T, Wu T-P, Wei Y-H (2014) Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress. Biochim Biophys Acta 1840(4):1331–1344. doi: 10.1016/j.bbagen.2013.10.034 CrossRefPubMedGoogle Scholar
  102. Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9(10):1102–1109. doi: 10.1038/ncb1007-1102 CrossRefPubMedGoogle Scholar
  103. Yoon M-S, Du G, Backer JM, Frohman MA, Chen J (2011) Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway. J Cell Biol 195(3):435–447. doi: 10.1083/jcb.201107033 PubMedCentralCrossRefPubMedGoogle Scholar
  104. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Lenardo MJ (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nat 465(7300):942–946. doi: 10.1038/nature09076 CrossRefGoogle Scholar
  105. Yuan. H.-X, Russell. R. C, Guan. K.-L (2013) Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 9(12): 1983–95. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24013218
  106. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Yue Z (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11(4):468–476. doi: 10.1038/ncb1854 PubMedCentralCrossRefPubMedGoogle Scholar
  107. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011a) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Sci (New york, N.Y.) 334(6056):678–683. doi: 10.1126/science.1207056 CrossRefGoogle Scholar
  108. Zoncu R, Efeyan A, Sabatini DM (2011b) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35. doi: 10.1038/nrm3025 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Claudio Marcelo Fader
    • 1
  • Milton Osmar Aguilera
    • 1
  • María Isabel Colombo
    • 1
  1. 1.Laboratorio de Biología Celular y Molecular, Instituto de Histología y Embriología (IHEM)-CONICET, Facultad de Ciencias MédicasUniversidad Nacional de CuyoMendozaArgentina

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