Autophagy Regulation of Bacterial Pathogen Invasion

  • Yuqing Lei
  • Huihui Li
  • Kefeng LuEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1209)


Autophagy pathway is highly conserved in all eukaryotic species and responsible for targeting of cytosol components, such as protein aggregates, damaged or unnecessary organelles, and intracellular bacterial pathogens for lysosome-dependent degradation. Besides severing as a catabolic process, autophagy pathway furthermore has been discovered to function pivotally in both innate and adaptive immune responses. At present, it has been well demonstrated that certain types of bacteria could be targeted by autophagy upon their invasion. However, several bacterial pathogens have developed strategies to evade this degradation and clearance. Here, we review the role and mechanism of autophagy in the regulation of bacteria invasion, which may facilitate the designing of clinical drugs for efficient and safe cure of infection diseases caused by toxic bacteria.


Autophagy Bacteria Invasion Degradation Exnophagy 



The authors thank members from K.F. Lu laboratory for advice and help in preparing the manuscript. The K.F. Lu laboratory was supported by the National Key R&D Program of China under grant 2017YFA0506300 (to K.L.) and the National Natural Science Foundation under grants 31770820 (to K.L.).


  1. 1.
    Abert C, Martens S (2019) Studies of receptor-Atg8 interactions during selective autophagy. Methods Mol Biol 1880:189–196PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Abreu S, Kriegenburg F, Gomez-Sanchez R, Mari M, Sanchez-Wandelmer J, Skytte RM, Soares GR, Zens B, Schuschnig M, Hardenberg R et al (2017) Conserved Atg8 recognition sites mediate Atg4 association with autophagosomal membranes and Atg8 deconjugation. EMBO Rep 18:765–780PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Backer JM (2016) The intricate regulation and complex functions of the class III phosphoinositide 3-kinase Vps34. Biochem J 473:2251–2271PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Behrends C, Fulda S (2012) Receptor proteins in selective autophagy. Int J Cell Biol 2012:673290PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bilanges B, Posor Y, Vanhaesebroeck B (2019) PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 20:515–534PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Biswas D, Qureshi OS, Lee WY, Croudace JE, Mura M, Lammas DA (2008) ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages. BMC Immunol 9:35PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Cappelletti C, Galbardi B, Kapetis D, Vattemi G, Guglielmi V, Tonin P, Salerno F, Morandi L, Tomelleri G, Mantegazza R et al (2014) Autophagy, inflammation and innate immunity in inflammatory myopathies. PLoS One 9:e111490PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Chaumorcel M, Souquere S, Pierron G, Codogno P, Esclatine A (2008) Human cytomegalovirus controls a new autophagy-dependent cellular antiviral defense mechanism. Autophagy 4:46–53PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Choi YB, Shembade N, Parvatiyar K, Balachandran S, Harhaj EW (2017) TAX1BP1 restrains virus-induced apoptosis by facilitating itch-mediated degradation of the mitochondrial adaptor MAVS. Mol Cell Biol 37Google Scholar
  10. 10.
    Choy A, Dancourt J, Mugo B, O’Connor TJ, Isberg RR, Melia TJ, Roy CR (2012) The legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338:1072–1076PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    De Paepe B, Creus KK, De Bleecker JL (2009) Role of cytokines and chemokines in idiopathic inflammatory myopathies. Curr Opin Rheumatol 21:610–616PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Deretic V (2012) Autophagy: an emerging immunological paradigm. J Immunol 189:15–20PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Dikic I, Elazar Z (2018) Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 19:349–364PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Dorn BR, Dunn WA, Progulske-Fox A (2001) Porphyromonas gingivalis traffics to autophagosomes in human coronary artery endothelial cells. Infect Immun 69:5698–5708PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Dortet L, Mostowy S, Louaka AS, Gouin E, Nahori M, Wiemer EAC, Dussurget O, Cossart P (2011) Recruitment of the major vault protein by InlK: a listeria monocytogenes strategy to avoid autophagy. Plos Pathog 7Google Scholar
  16. 16.
    English L, Chemali M, Duron J, Rondeau C, Laplante A, Gingras D, Alexander D, Leib D, Norbury C, Lippe R et al (2009) Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10:480–487PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Filomeni G, De Zio D, Cecconi F (2015) Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ 22:377–388PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Franco LH, Nair VR, Scharn CR, Xavier RJ, Torrealba JR, Shiloh MU, Levine B (2017) The ubiquitin ligase Smurf1 functions in selective autophagy of mycobacterium tuberculosis and anti-tuberculous host defense. Cell Host Microbe 22:421–423PubMedCrossRefGoogle Scholar
  19. 19.
    Fujioka Y, Suzuki SW, Yamamoto H, Kondo-Kakuta C, Kimura Y, Hirano H, Akada R, Inagaki F, Ohsumi Y, Noda NN (2014) Structural basis of starvation-induced assembly of the autophagy initiation complex. Nat Struct Mol Biol 21:513–521PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Gadhave K, Bolshette N, Ahire A, Pardeshi R, Thakur K, Trandafir C, Istrate A, Ahmed S, Lahkar M, Muresanu DF et al (2016) The ubiquitin proteasomal system: a potential target for the management of Alzheimer’s disease. J Cell Mol Med 20:1392–1407PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ge L, Melville D, Zhang M, Schekman R (2013) The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. Elife 2:e947CrossRefGoogle Scholar
  22. 22.
    Gluschko A, Herb M, Wiegmann K, Krut O, Neiss WF, Utermohlen O, Kronke M, Schramm M (2018) The beta2 Integrin Mac-1 Induces Protective LC3-associated phagocytosis of listeria monocytogenes. Cell Host Microbe 23:324–337PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    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 119:753–766PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Hashimoto K, Simmons AN, Kajino-Sakamoto R, Tsuji Y, Ninomiya-Tsuji J (2016) TAK1 regulates the Nrf2 antioxidant system through modulating p62/SQSTM1. Antioxid Redox Sig 25:953–964CrossRefGoogle Scholar
  25. 25.
    Hayashi K, Taura M, Iwasaki A (2018) The interaction between IKKalpha and LC3 promotes type I interferon production through the TLR9-containing LAPosome. Sci Sig 11Google Scholar
  26. 26.
    Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW (2015) The PINK1-PARKIN Mitochondrial ubiquitination pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol Cell 60:7–20PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Itakura E, Kishi-Itakura C, Mizushima N (2012) The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151:1256–1269PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Jin M, Klionsky DJ (2014) Regulation of autophagy: modulation of the size and number of autophagosomes. FEBS Lett 588:2457–2463PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kim YM, Jung CH, Seo M, Kim EK, Park JM, Bae SS, Kim DH (2015) mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol Cell 57:207–218PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Levine B, Liu R, Dong X, Zhong Q (2015) Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology. Trends Cell Biol 25:533–544PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Levine B, Kroemer G (2019) Biological functions of autophagy genes: a disease perspective. Cell 176:11–42PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Liu W, Jiang Y, Sun J, Geng S, Pan Z, Prinz RA, Wang C, Sun J, Jiao X, Xu X (2018) Activation of TGF-beta-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy. Cell Death Dis 9:570PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Martinez J, Almendinger J, Oberst A, Ness R, Dillon CP, Fitzgerald P, Hengartner MO, Green DR (2011) Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. Proc Natl Acad Sci USA 108:17396–17401PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Martinez J, Malireddi RKS, Lu Q, Cunha LD, Pelletier S, Gingras S, Orchard R, Guan J, Tan H, Peng J et al (2015) Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol 17:893–906PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D, Coxon FP, Miranda DSD, Bhogaraju S, Maddi K et al (2015) PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol Cell 57:39–54PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Minowa-Nozawa A, Nozawa T, Okamoto-Furuta K, Kohda H, Nakagawa I (2017) Rab35 GTPase recruits NDP52 to autophagy targets. EMBO J 36:3405PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132PubMedCrossRefGoogle Scholar
  38. 38.
    Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K et al (2004) Autophagy defends cells against invading group A Streptococcus. Science 306:1037–1040PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Nakamura S, Yoshimori T (2017) New insights into autophagosome-lysosome fusion. J Cell Sci 130:1209–1216PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10:458–467PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Nguyen TD, Shaid S, Vakhrusheva O, Koschade SE, Klann K, Tholken M, Baker F, Zhang J, Oellerich T, Surun D et al (2019) Loss of the selective autophagy receptor p62 impairs murine myeloid leukemia progression and mitophagy. Blood 133:168–179PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Nozawa T, Aikawa C, Goda A, Maruyama F, Hamada S, Nakagawa I (2012) The small GTPases Rab9A and Rab23 function at distinct steps in autophagy during group A Streptococcus infection. Cell Microbiol 14:1149–1165PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Ogawa M, Yoshikawa Y, Kobayashi T, Mimuro H, Fukumatsu M, Kiga K, Piao Z, Ashida H, Yoshida M, Kakuta S et al (2011) A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens. Cell Host Microbe 9:376–389PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2:211–216PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Peng H, Yang J, Li G, You Q, Han W, Li T, Gao D, Xie X, Lee BH, Du J et al (2017) Ubiquitination of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. Cell Res 27:657–674PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Periyasamy-Thandavan S, Jiang M, Schoenlein P, Dong Z (2009) Autophagy: molecular machinery, regulation, and implications for renal pathophysiology. Am J Physiol Renal Physiol 297:F244–F256PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Petkova DS, Verlhac P, Rozieres A, Baguet J, Claviere M, Kretz-Remy C, Mahieux R, Viret C, Faure M (2017) Distinct contributions of autophagy receptors in measles virus replication. Viruses 9Google Scholar
  48. 48.
    Piano ME, Folgiero V, Marcellini V, Romania P, Bellacchio E, D’Alicandro V, Bocci C, Carrozzo R, Martinelli D, Petrini S et al (2018) The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. Autophagy 14:22–37CrossRefGoogle Scholar
  49. 49.
    Py BF, Lipinski MM, Yuan J (2007) Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3:117–125PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Reggiori F, Klionsky DJ (2013) Autophagic processes in yeast: mechanism, machinery and regulation. Genetics 194:341–361PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Rodrigues PH, Belanger M Jr, Dunn W, Progulske-Fox A (2008) Porphyromonas gingivalis and the autophagic pathway: an innate immune interaction? Front Biosci-Landmrk 13:178–187PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Rogov V, Dotsch V, Johansen T, Kirkin V (2014) Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell 53:167–178PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Romao S, Gasser N, Becker AC, Guhl B, Bajagic M, Vanoaica D, Ziegler U, Roesler J, Dengjel J, Reichenbach J et al (2013) Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing. J Cell Biol 203:757–766PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Ryabovol VV, Minibayeva FV (2016) Molecular mechanisms of autophagy in plants: role of ATG8 proteins in formation and functioning of autophagosomes. Biochem (Mosc) 81:348–363CrossRefGoogle Scholar
  55. 55.
    Sakurai A, Maruyama F, Funao J, Nozawa T, Aikawa C, Okahashi N, Shintani S, Hamada S, Ooshima T, Nakagawa I (2010) Specific behavior of intracellular Streptococcus pyogenes that has undergone autophagic degradation is associated with bacterial streptolysin O and host small G proteins Rab5 and Rab7. J Biol Chem 285:22666–22675PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Slowicka K, Vereecke L, Mc GC, Sze M, Maelfait J, Kolpe A, Saelens X, Beyaert R, van Loo G (2016) Optineurin deficiency in mice is associated with increased sensitivity to Salmonella but does not affect proinflammatory NF-kappaB signaling. Eur J Immunol 46:971–980PubMedCrossRefGoogle Scholar
  57. 57.
    Slowicka K, van Loo G (2018) Optineurin functions for optimal immunity. Front Immunol 9:769PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Suzuki H, Osawa T, Fujioka Y, Noda NN (2017) Structural biology of the core autophagy machinery. Curr Opin Struct Biol 43:10–17PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Thurston TL, Wandel MP, von Muhlinen N, Foeglein A, Randow F (2012) Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482:414–418PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Tilija PN, Park PH (2017) Role of p62 in the suppression of inflammatory cytokine production by adiponectin in macrophages: involvement of autophagy and p21/Nrf2 axis. Sci Rep 7:393CrossRefGoogle Scholar
  61. 61.
    Tumbarello DA, Manna PT, Allen M, Bycroft M, Arden SD, Kendrick-Jones J, Buss F (2015) The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella Typhimurium by autophagy. PLoS Pathog 11:e1005174PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Wan W, You Z, Zhou L, Xu Y, Peng C, Zhou T, Yi C, Shi Y, Liu W (2018) mTORC1-regulated and HUWE1-mediated WIPI2 degradation controls autophagy flux. Mol Cell 72:303–315PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Watson RO, Manzanillo PS, Cox JS (2012) Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150:803–815PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Wen X, Klionsky DJ (2016) An overview of macroautophagy in yeast. J Mol Biol 428:1681–1699PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Xu Y, Eissa NT (2010) Autophagy in innate and adaptive immunity. Proc Am Thorac Soc 7:22–28PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Yano T, Mita S, Ohmori H, Oshima Y, Fujimoto Y, Ueda R, Takada H, Goldman WE, Fukase K, Silverman N et al (2008) Autophagic control of listeria through intracellular innate immune recognition in drosophila. Nat Immunol 9:908–916PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Yue C, Li J, Jin H, Hua K, Zhou W, Wang Y, Cheng G, Liu D, Xu L, Chen Y et al (2019) Autophagy is a defense mechanism inhibiting invasion and inflammation during high-virulent haemophilus parasuis infection in PK-15 cells. Front Cell Infect Microbiol 9:93PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Zhao YG, Zhang H (2019) Autophagosome maturation: an epic journey from the ER to lysosomes. J Cell Biol 218:757–770PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Zheng YT, Shahnazari S, Brech A, Lamark T, Johansen T, Brumell JH (2009) The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J Immunol 183:5909–5916PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Neurosurgery, State Key Laboratory of Biotherapy, Collaborative Innovation Center for BiotherapyWest China Hospital, Sichuan UniversityChengduChina
  2. 2.State Key Laboratory of BiotherapyWest China Second University Hospital, Sichuan UniversityChengduChina

Personalised recommendations