Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 141 No. 1920 (2011)

Autophagy of pathogens alarms the immune system and participates in its effector functions

  • S Romao
  • C Münz
DOI
https://doi.org/10.4414/smw.2011.13198
Cite this as:
Swiss Med Wkly. 2011;141:w13198
Published
09.05.2011

Summary

Macroautophagy is a main catabolic pathway of eukaryotic cells, delivering cytoplasmic constituents for lysosomal degradation. Originally described as a starvation response, it has now been realised that macroautophagy supports many aspects of innate and adaptive immunity by facilitating innate pathogen detection and antigen presentation, as well as pathogen clearance and lymphocyte expansion. In the first half of this review, we summarise new insights into substrate selection and macroautophagic support of vesicular transport pathways, which underlie macroautophagic regulation of afferent and efferent immunity to pathogens, as outlined in the second half of the review. Applying this increased mechanistic understanding to infectious disease settings should allow us to identify further pathways for pathogen restriction, which can be explored for therapeutic manipulations of macro-autophagy.

References

  1. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, et al. Autophagy defends cells against invading group A Streptococcus. Science. 2004;306(5698):1037–40.
  2. Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007;7(10):767–77.
  3. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011;469(7330):323–35.
  4. Klionsky DJ, Codogno P, Cuervo AM, Deretic V, Elazar Z, Fueyo-Margareto J, Gewirtz DA, Kroemer G, Levine B, Mizushima N, Rubinsztein DC, Thumm M, Tooze SA. A comprehensive glossary of autophagy-related molecules and processes. Autophagy. 2010;6(4).
  5. Münz C. Enhancing immunity through autophagy. Annu Rev Immunol. 2009;27:423–9.
  6. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol. 2009 Dec;11(12):1433–7.
  7. Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy. 2009;5(8):1180–5.
  8. Yen WL, Shintani T, Nair U, Cao Y, Richardson BC, et al. The conserved oligomeric Golgi complex is involved in double-membrane vesicle formation during autophagy. J Cell Biol. 2010;188(1):101–14.
  9. Lynch-Day MA, Bhandari D, Menon S, Huang J, Cai H, Bartholomew CR, Brumell JH, Ferro-Novick S, Klionsky DJ. Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy. Proc Natl Acad Sci U S A. 2010;107(17):7811–6.
  10. English L, Chemali M, Duron J, Rondeau C, Laplante A, et al. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol. 2009;10(5):480–7.
  11. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. 2010;141(4):656–67.
  12. He C, Song H, Yorimitsu T, Monastyrska I, Yen WL, Legakis JE, Klionsky DJ. Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast. J Cell Biol. 2006;175(6):925–35.
  13. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol. 2010;12(8):747–57.
  14. Gannage M, Rämer PC, Münz C. Targeting Beclin 1 for viral subversion of macroautophagy. Autophagy. 2010;6(1):166–7.
  15. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B. Bcl-2 antiapoptotic proteins inhibit Beclin 1–dependent autophagy. Cell. 2005;122(6):927–39.
  16. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100(25):15077–82.
  17. Nakatogawa H, Ichimura Y, Ohsumi Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell. 2007;130(1):165–78.
  18. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005;171(4):603–14.
  19. Kristensen AR, Schandorff S, Hoyer-Hansen M, Nielsen MO, Jaattela M, et al. Ordered organelle degradation during starvation-induced autophagy. Mol Cell Proteomics. 2008;7(12):2419–28.
  20. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282(33):24131–45.
  21. Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL, Bruun JA, Shvets E, McEwan DG, Clausen TH, Wild P, Bilusic I, Theurillat JP, Overvatn A, Ishii T, Elazar Z, Komatsu M, et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009;33(4):505–16.
  22. Thurston TL, Ryzhakov G, Bloor S, von Muhlinen N, Randow F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol. 2009;10(11):1215–21.
  23. Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. Embo J. 2009;28(7):889–901.
  24. Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, et al. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010;20(2):143–8.
  25. Carra S, Seguin SJ, Lambert H, Landry J. HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. J Biol Chem. 2008;283(3):1437–44.
  26. Kettern N, Rogon C, Limmer A, Schild H, Hohfeld J. The Hsc/Hsp70 Co-Chaperone Network Controls Antigen Aggregation and Presentation during Maturation of Professional Antigen Presenting Cells. PLoS ONE. 2011;6(1):e16398.
  27. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131(6):1149–63.
  28. Simonsen A, Birkeland HC, Gillooly DJ, Mizushima N, Kuma A, et al. Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J Cell Sci. 2004;117(Pt 18):4239–51.
  29. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8(1):e1000298.
  30. Kraft C, Peter M, Hofmann K. Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol. 2010;12(9):836–41.
  31. Kraft C, Deplazes A, Sohrmann M, Peter M. Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nat Cell Biol. 2008;10(5):602–10.
  32. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.
  33. Okamoto K, Kondo-Okamoto N, Ohsumi Y. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell. 2009;17(1):87–97.
  34. Kanki T, Wang K, Cao Y, Baba M, Klionsky DJ. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell. 2009;17(1):98–109.
  35. Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, Chen M, Wang J. Essential role for Nix in autophagic maturation of erythroid cells. Nature. 2008 May 4.
  36. Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, Dorsey FC, Kundu M, Opferman JT, Cleveland JL, Miller JL, Ney PA. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci U S A. 2007;104(49):19500–5.
  37. Anitei M, Wassmer T, Stange C, Hoflack B. Bidirectional transport between the trans-Golgi network and the endosomal system. Mol Membr Biol. 2010;27(8):443–56.
  38. Longatti A, Orsi A, Tooze SA. Autophagosome formation: not necessarily an inside job. Cell Res. 2010;20(11):1181–4.
  39. Backer JM. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J. 2008;410(1):1–17.
  40. Ravikumar B, Imarisio S, Sarkar S, O’Kane CJ, Rubinsztein DC. Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci. 2008;121(Pt 10):1649–60.
  41. Fader CM, Sanchez D, Furlan M, Colombo MI. Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in K562 cells. Traffic. 2008;9(2):230–50.
  42. Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen EL. Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci. 2004;117(Pt 20):4837–48.
  43. Duran JM, Anjard C, Stefan C, Loomis WF, Malhotra V. Unconventional secretion of Acb1 is mediated by autophagosomes. J Cell Biol. 2010;188(4):527–36.
  44. Manjithaya R, Anjard C, Loomis WF, Subramani S. Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation. J Cell Biol. 2010 Feb 22;188(4):537–46.
  45. Taylor MP, Burgon TB, Kirkegaard K, Jackson WT. Role of microtubules in extracellular release of poliovirus. J Virol. 2009;83(13):6599–609.
  46. Jiang H, White EJ, Gomez-Manzano C, Fueyo J. Adenovirus’s last trick: you say lysis, we say autophagy. Autophagy. 2008;4(1):118–20.
  47. Kyei GB, Dinkins C, Davis AS, Roberts E, Singh SB, Dong C, Wu L, Kominami E, Ueno T, Yamamoto A, Federico M, Panganiban A, Vergne I, Deretic V. Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J Cell Biol. 2009;186(2):255–68.
  48. de Haan CA, Molinari M, Reggiori F. Autophagy-independent LC3 function in vesicular traffic. Autophagy. 2010;6(7):994–6.
  49. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature. 2007;450(7173):1253–7.
  50. Andrade RM, Wessendarp M, Gubbels MJ, Striepen B, Subauste CS. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J Clin Invest. 2006;116(9):2366–77.
  51. Meyer-Morse N, Robbins JR, Rae CS, Mochegova SN, Swanson MS, Zhao Z, Virgin HW, Portnoy D. Listeriolysin O is necessary and sufficient to induce autophagy during Listeria monocytogenes infection. PLoS ONE 2010;5(1):e8610.
  52. Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M, Kim M, Mimuro H, Nakagawa I, Yanagawa T, Ishii T, Kakizuka A, Sztul E, Chakraborty T, Sasakawa C. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat Cell Biol. 2009;11(10):1233–40.
  53. Ogawa M, Yoshimori T, Suzuki T, Sagara H, Mizushima N, Sasakawa C. Escape of Intracellular Shigella from Autophagy. Science. 2005;307(5710):727–31.
  54. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages. Cell. 2004;119(6):753–66.
  55. Intemann CD, Thye T, Niemann S, Browne EN, Amanua Chinbuah M, Enimil A, Gyapong J, Osei I, Owusu-Dabo E, Helm S, Rusch-Gerdes S, Horstmann RD, Meyer CG. Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog. 2009;5(9):e1000577.
  56. Kumar D, Nath L, Kamal MA, Varshney A, Jain A, Singh S, Rao KV. Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell. 2010;140(5):731–43.
  57. Ling YM, Shaw MH, Ayala C, Coppens I, Taylor GA, Ferguson DJ, Yap GS. Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J Exp Med. 2006 Sep 4;203(9):2063–71.
  58. Alonso S, Pethe K, Russell DG, Purdy GE. Lysosomal killing of Mycobacterium mediated by ubiquitin-derived peptides is enhanced by autophagy. Proc Natl Acad Sci U S A. 2007;104(14):6031–6.
  59. Ponpuak M, Davis AS, Roberts EA, Delgado MA, Dinkins C, Zhao Z, Virgin HWt, Kyei GB, Johansen T, Vergne I, Deretic V. Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties. Immunity. 2010 Mar 26;32(3):329–41.
  60. Liu Y, Schiff M, Czymmek K, Talloczy Z, Levine B, Dinesh-Kumar SP. Autophagy regulates programmed cell death during the plant innate immune response. Cell. 2005;121(4):567–77.
  61. Shelly S, Lukinova N, Bambina S, Berman A, Cherry S. Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus. Immunity. 2009;30(4):588–98.
  62. Orvedahl A, Alexander D, Talloczy Z, Sun Q, Wei Y, Zhang W, Burns D, Leib D, Levine B. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host & Microbe. 2007;1:23–35.
  63. Orvedahl A, MacPherson S, Sumpter R, Jr., Talloczy Z, Zou Z, Levine B. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe. 2010;7(2):115–27.
  64. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007 Mar 9;315(5817):1398–401.
  65. Chaturvedi A, Dorward D, Pierce SK. The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyperresponses to DNA-containing antigens. Immunity. 2008;28(6):799–809.
  66. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, Ishii KJ, Kawai T, Akira S, Suzuki K, Okuda K. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci U S A. 2007;104(35):14050–5.
  67. Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci U S A. 2009;106(8):2770–5.
  68. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008 Oct 5.
  69. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–5.
  70. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.
  71. Dupont N, Lacas-Gervais S, Bertout J, Paz I, Freche B, Van Nhieu GT, van der Goot FG, Sansonetti PJ, Lafont F. Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy. Cell Host Microbe. 2009 Aug 20;6(2):137–49.
  72. Delgado MA, Elmaoued RA, Davis AS, Kyei G, Deretic V. Toll-like receptors control autophagy. Embo J. 2008;27(7):1110–21.
  73. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007;27(1):135–44.
  74. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16(1):90–7.
  75. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, Gunther S, Prescott NJ, Onnie CM, Hasler R, Sipos B, Folsch UR, Lengauer T, Platzer M, Mathew CG, Krawczak M, Schreiber S. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39(2):207–11.
  76. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39(5):596–604.
  77. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411(6837):599–603.
  78. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411(6837):603–6.
  79. Schmid D, Pypaert M, Münz C. MHC class II antigen loading compartments continuously receive input from autophagosomes. Immunity. 2007;26:79–92.
  80. Brazil MI, Weiss S, Stockinger B. Excessive degradation of intracellular protein in macrophages prevents presentation in the context of major histocompatibility complex class II molecules. Eur J Immunol. 1997;27(6):1506–14.
  81. Nimmerjahn F, Milosevic S, Behrends U, Jaffee EM, Pardoll DM, Bornkamm GW, Mautner J. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur J Immunol. 2003;33(5):1250–9.
  82. Riedel A, Nimmerjahn F, Burdach S, Behrends U, Bornkamm GW, Mautner J. Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1–mediated nuclear export. Eur J Immunol. 2008;38(8):2090–5.
  83. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, Münz C. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science. 2005;307(5709):593–6.
  84. Leung CS, Haigh TA, Mackay LK, Rickinson AB, Taylor GS. Nuclear location of an endogenously expressed antigen, EBNA1, restricts access to macroautophagy and the range of CD4 epitope display. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2165–70.
  85. Taylor GS, Mautner J, Münz C. Autophagy in herpesvirus immune control and immune escape. Herpesviridae. 2010;2(1):2.
  86. Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL, Jr., Eissa NT. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009;15(3):267–76.
  87. Russmann H, Panthel K, Kohn B, Jellbauer S, Winter SE, Garbom S, Wolf-Watz H, Hoffmann S, Grauling-Halama S, Geginat G. Alternative endogenous protein processing via an autophagy-dependent pathway compensates for Yersinia-mediated inhibition of endosomal major histocompatibility complex class II antigen presentation. Infect Immun. 2010;78(12):5138–50.
  88. Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Muller M, Kreymborg K, Altenberend F, Brandenburg J, Kalbacher H, Brock R, Driessen C, Rammensee HG, Stevanovic S. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A. 2005;102:7922–7.
  89. Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature. 2008;455(7211):396–400.
  90. Lee HK, Mattei LM, Steinberg BE, Alberts P, Lee YH, Chervonsky A, Mizushima N, Grinstein S, Iwasaki A. In vivo requirement for Atg5 in antigen presentation by dendritic cells. Immunity. 2010;32(2):227–39.
  91. Leib DA, Alexander DE, Cox D, Yin J, Ferguson TA. Interaction of ICP34.5 with Beclin 1 modulates herpes simplex virus type 1 pathogenesis through control of CD4+ T-cell responses. J Virol. 2009;83(23):12164–71.
  92. Li Y, Wang LX, Yang G, Hao F, Urba WJ, Hu HM. Efficient cross-presentation depends on autophagy in tumor cells. Cancer Res. 2008;68(17):6889–95.
  93. Uhl M, Kepp O, Jusforgues-Saklani H, Vicencio JM, Kroemer G, Albert ML. Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell Death Differ. 2009;16(7):991–1005.
  94. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med. 2007;204(1):25–31.
  95. Pua HH, Guo J, Komatsu M, He YW. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J Immunol. 2009;182(7):4046–55.
  96. Jia W, Pua HH, Li QJ, He YW. Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes. J Immunol. 2011;186(3):1564–74.
  97. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, et al. The autophagy gene ATG5 plays an essential role in B lymphocyte development. Autophagy. 2008;4(3):309–14.
  98. Mortensen M, Soilleux EJ, Djordjevic G, Tripp R, Lutteropp M, Sadighi-Akha E, Stranks AJ, Glanville J, Knight S, SE WJ, Kranc KR, Simon AK. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med. 2011 Feb 21.
  99. Arsov I, Adebayo A, Kucerova-Levisohn M, Haye J, MacNeil M, Papavasiliou FN, Yue Z, Ortiz BD. A role for autophagic protein Beclin 1 early in lymphocyte development. J Immunol. 2011;186(4):2201–9.
  100. Arsov I, Li X, Matthews G, Coradin J, Hartmann B, Simon AK, Sealfon SC, Yue Z. BAC-mediated transgenic expression of fluorescent autophagic protein Beclin 1 reveals a role for Beclin 1 in lymphocyte development. Cell Death Differ. 2008;15(9):1385–95.
  101. Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D, Miller BC, Cadwell K, Delgado MA, Ponpuak M, Green KG, Schmidt RE, Mizushima N, Deretic V, Sibley LD, Virgin HW. Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe. 2008;4(5):458–69.