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  • Review Article
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Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?

Nature Reviews Microbiology volume 13, pages 71–82 (2015)Cite this article

Subjects

Key Points

  • The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the endoplasmic reticulum (ER). The UPR is also invoked in innate immune signalling in response to invading microorganisms.

  • Several intracellular bacterial pathogens exploit the host secretory pathway to generate replication-permissive vacuoles that are derived from, or that closely interact with, the ER. Their resulting proliferation in the ER can elicit the UPR.

  • Intracellular bacteria can either induce or downregulate the UPR to promote their survival, possibly via the concerted action of various effector molecules.

  • ER stress and innate immune signalling pathways intersect in the control of inflammatory responses to invading microorganisms. In this context, the UPR can directly detect bacterial toxins or effectors, or can sense and respond to cellular alterations that are caused by these pathogenic molecules, which leads to the activation of pro-inflammatory responses that provide protection against bacterial infections.

  • Bacterial pathogens have evolved molecular mechanisms that mitigate or exploit the UPR to promote their intracellular survival and proliferation.

Abstract

The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the endoplasmic reticulum (ER), which also invokes innate immune signalling in response to invading microorganisms. Although it has been known for some time that the UPR is modulated by various viruses, recent evidence indicates that it also has multiple roles during bacterial infections. In this Review, we describe how bacteria interact with the ER, including how bacteria induce the UPR, how subversion of the UPR promotes bacterial proliferation and how the UPR contributes to innate immune responses against invading bacteria.

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Figure 1: Cellular responses to endoplasmic reticulum stress.
Figure 2: Trafficking and biogenesis of endoplasmic reticulum-associated replicative organelles by bacterial pathogens.
Figure 3: Induction of the unfolded protein response and inflammation by bacterial virulence factors.

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References

  1. Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011). This is an excellent current review of the UPR.

    CAS  PubMed  Google Scholar 

  2. Cho, J. A. et al. The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13, 558–569 (2013). This paper shows that generation of RNA fragments by IRE1 in response to toxin translocation to the ER activates innate immune responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. He, B. Viruses, endoplasmic reticulum stress, and interferon responses. Cell Death Differ. 13, 393–403 (2006).

    CAS  PubMed  Google Scholar 

  4. Schroder, M. & Kaufman, R. J. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789 (2005).

    PubMed  Google Scholar 

  5. Zhang, K. & Kaufman, R. J. From endoplasmic-reticulum stress to the inflammatory response. Nature 454, 455–462 (2008). This is an excellent investigation of the links between ER stress and inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gardner, B. M. & Walter, P. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 333, 1891–1894 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Olzmann, J. A., Kopito, R. R. & Christianson, J. C. The mammalian endoplasmic reticulum-associated degradation system. Cold Spring Harb. Perspect. Biol. 5, a013185 (2013).

    PubMed  PubMed Central  Google Scholar 

  8. Bertolotti, A., Zhang, Y., Hendershot, L. M., Harding, H. P. & Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biol. 2, 326–332 (2000).

    CAS  PubMed  Google Scholar 

  9. Kimata, Y., Oikawa, D., Shimizu, Y., Ishiwata-Kimata, Y. & Kohno, K. A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1. J. Cell Biol. 167, 445–456 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Pincus, D. et al. BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol. 8, e1000415 (2010).

    PubMed  PubMed Central  Google Scholar 

  11. Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. M. & Walter, P. Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb. Perspect. Biol. 5, a013169 (2013). This is an excellent current review of how the UPR is initiated.

    PubMed  PubMed Central  Google Scholar 

  12. Lee, K. et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 16, 452–466 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lee, A. H., Iwakoshi, N. N. & Glimcher, L. H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448–7459 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hollien, J. et al. Regulated IRE1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186, 323–331 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hollien, J. & Weissman, J. S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104–107 (2006).

    CAS  PubMed  Google Scholar 

  16. Harding, H. P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274 (1999).

    CAS  PubMed  Google Scholar 

  17. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    CAS  PubMed  Google Scholar 

  18. Urra, H., Dufey, E., Lisbona, F., Rojas-Rivera, D. & Hetz, C. When ER stress reaches a dead end. Biochim. Biophys. Acta 1833, 3507–3517 (2013).

    CAS  PubMed  Google Scholar 

  19. Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Adachi, Y. et al. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct. Function 33, 75–89 (2008).

    CAS  Google Scholar 

  21. Wu, J. et al. ATF6α optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell 13, 351–364 (2007).

    CAS  PubMed  Google Scholar 

  22. Yamamoto, K. et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev. Cell 13, 365–376 (2007).

    CAS  PubMed  Google Scholar 

  23. Bernales, S., McDonald, K. L. & Walter, P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, e423 (2006).

    PubMed  PubMed Central  Google Scholar 

  24. Bommiasamy, H. et al. ATF6α induces XBP1-independent expansion of the endoplasmic reticulum. J. Cell Sci. 122, 1626–1636 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Schuck, S., Prinz, W. A., Thorn, K. S., Voss, C. & Walter, P. Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J. Cell Biol. 187, 525–536 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26, 9220–9231 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ding, W. X. et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J. Biol. Chem. 282, 4702–4710 (2007).

    CAS  PubMed  Google Scholar 

  28. Urano, F. et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664–666 (2000). This paper shows that IRE1 links ER stress to JNK, which is an activator of AP-1.

    CAS  PubMed  Google Scholar 

  29. Detilleux, P. G., Deyoe, B. L. & Cheville, N. F. Entry and intracellular localization of Brucella spp. in Vero cells: fluorescence and electron microscopy. Vet. Pathol. 27, 317–328 (1990).

    CAS  PubMed  Google Scholar 

  30. Detilleux, P. G., Deyoe, B. L. & Cheville, N. F. Penetration and intracellular growth of Brucella abortus in nonphagocytic cells in vitro. Infect. Immun. 58, 2320–2328 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Horwitz, M. A. Formation of a novel phagosome by the Legionnaires' disease bacterium (Legionella pneumophila) in human monocytes. J. Exp. Med. 158, 1319–1331 (1983).

    CAS  PubMed  Google Scholar 

  32. Pizarro-Cerdá, J. et al. Brucella abortus transits through the autophagic pathway and replicates in the endoplasmic reticulum of nonprofessional phagocytes. Infect. Immun. 66, 5711–5724 (1998).

    PubMed  PubMed Central  Google Scholar 

  33. Pizarro-Cerdá, J., Moreno, E., Sanguedolce, V., Mege, J. L. & Gorvel, J. P. Virulent Brucella abortus prevents lysosome fusion and is distributed within autophagosome-like compartments. Infect. Immun. 66, 2387–2392 (1998).

    PubMed  PubMed Central  Google Scholar 

  34. Tilney, L. G., Harb, O. S., Connelly, P. S., Robinson, C. G. & Roy, C. R. How the parasitic bacterium Legionella pneumophila modifies its phagosome and transforms it into rough ER: implications for conversion of plasma membrane to the ER membrane. J. Cell. Sci. 114, 4637–4650 (2001).

    CAS  PubMed  Google Scholar 

  35. Celli, J. et al. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J. Exp. Med. 198, 545–556 (2003). This paper provides evidence that Brucella spp. exploits the ER via its VirB T4SS to evade killing by macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Robinson, C. G. & Roy, C. R. Attachment and fusion of endoplasmic reticulum with vacuoles containing Legionella pneumophila. Cell. Microbiol. 8, 793–805 (2006).

    CAS  PubMed  Google Scholar 

  37. Asare, R. & Abu Kwaik, Y. Early trafficking and intracellular replication of Legionella longbeachaea within an ER-derived late endosome-like phagosome. Cell. Microbiol. 9, 1571–1587 (2007).

    CAS  PubMed  Google Scholar 

  38. Derré, I., Swiss, R. & Agaisse, H. The lipid transfer protein CERT interacts with the Chlamydia inclusion protein IncD and participates to ER-Chlamydia inclusion membrane contact sites. PLoS Pathog. 7, e1002092 (2011).

    PubMed  PubMed Central  Google Scholar 

  39. Dumoux, M., Clare, D. K., Saibil, H. R. & Hayward, R. D. Chlamydiae assemble a pathogen synapse to hijack the host endoplasmic reticulum. Traffic 13, 1612–1627 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mehlitz, A. et al. The chlamydial organism Simkania negevensis forms ER vacuole contact sites and inhibits ER-stress. Cell. Microbiol. 16, 1224–1243 (2014). This paper identifies a new bacterial pathogen that associates with the ER.

    CAS  PubMed  Google Scholar 

  41. Kagan, J. C. & Roy, C. R. Legionella phagosomes intercept vesicular traffic from endoplasmic reticulum exit sites. Nature Cell Biol. 4, 945–954 (2002). This paper shows that Legionella spp. recruit early secretory vesicles after internalization by phagocytic cells.

    CAS  PubMed  Google Scholar 

  42. Starr, T. et al. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe 11, 33–45 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Celli, J., Salcedo, S. P. & Gorvel, J.-P. Brucella coopts the small GTPase Sar1 for intracellular replication. Proc. Natl Acad. Sci. USA 102, 1673–1678 (2005). This paper provides evidence that B. abortus intercepts traffic from ERESs to promote its intracellular replication.

    CAS  PubMed  Google Scholar 

  44. Porte, F., Liautard, J. P. & Köhler, S. Early acidification of phagosomes containing Brucella suis is essential for intracellular survival in murine macrophages. Infect. Immun. 67, 4041–4047 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Starr, T., Ng, T. W., Wehrly, T. D., Knodler, L. A. & Celli, J. Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment. Traffic 9, 678–694 (2008).

    CAS  PubMed  Google Scholar 

  46. Robertson, D. K., Gu, L., Rowe, R. K. & Beatty, W. L. Inclusion biogenesis and reactivation of persistent Chlamydia trachomatis requires host cell sphingolipid biosynthesis. PLoS Pathog. 5, e1000664 (2009).

    PubMed  PubMed Central  Google Scholar 

  47. van Ooij, C. et al. Host cell-derived sphingolipids are required for the intracellular growth of Chlamydia trachomatis. Cell. Microbiol. 2, 627–637 (2000).

    CAS  PubMed  Google Scholar 

  48. Machner, M. P. & Isberg, R. R. Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev. Cell 11, 47–56 (2006).

    CAS  PubMed  Google Scholar 

  49. Murata, T. et al. The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nature Cell Biol. 8, 971–977 (2006). References 48 and 49 show that Legionella spp. translocates a GEF into infected cells to manipulate ER-to-Golgi traffic.

    CAS  PubMed  Google Scholar 

  50. Ingmundson, A., Delprato, A., Lambright, D. G. & Roy, C. R. Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature 450, 365–369 (2007).

    CAS  PubMed  Google Scholar 

  51. Arasaki, K. & Roy, C. R. Legionella pneumophila promotes functional interactions between plasma membrane syntaxins and Sec22b. Traffic 11, 587–600 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Arasaki, K., Toomre, D. K. & Roy, C. R. The Legionella pneumophila effector DrrA is sufficient to stimulate SNARE-dependent membrane fusion. Cell Host Microbe 11, 46–57 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Nagai, H. A. Bacterial guanine nucleotide exchange factor activates ARF on Legionella phagosomes. Science 295, 679–682 (2002).

    CAS  PubMed  Google Scholar 

  54. Dorer, M. S., Kirton, D., Bader, J. S. & Isberg, R. R. RNA interference analysis of Legionella in Drosophila cells: exploitation of early secretory apparatus dynamics. PLoS Pathog. 2, e34 (2006).

    PubMed  PubMed Central  Google Scholar 

  55. Comerci, D. J., Lorenzo, M. M., Sieira, R., Gorvel, J.-P. & Ugalde, R. A. Essential role of the VirB machinery in the maturation of the Brucella abortus-containing vacuole. Cell. Microbiol. 3, 159–168 (2001).

    CAS  PubMed  Google Scholar 

  56. Boschiroli, M. L. The Brucella suis virB operon is induced intracellularly in macrophages. Proc. Natl Acad. Sci. 99, 1544–1549 (2002).

    CAS  PubMed  Google Scholar 

  57. de Jong, M. F., Sun, Y. H., den Hartigh, A. B., van Dijl, J. M. & Tsolis, R. M. Identification of VceA and VceC, two members of the VjbR regulon that are translocated into macrophages by the Brucella type IV secretion system. Mol. Microbiol. 70, 1378–1396 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. de Barsy, M. et al. Identification of a Brucella spp. secreted effector specifically interacting with human small GTPase Rab2. Cell. Microbiol. 13, 1044–1058 (2011).

    CAS  PubMed  Google Scholar 

  59. Marchesini, M. I., Herrmann, C. K., Salcedo, S. P., Gorvel, J.-P. & Comerci, D. J. In search of Brucella abortus type IV secretion substrates: screening and identification of four proteins translocated into host cells through VirB system. Cell. Microbiol. 13, 1261–1274 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Myeni, S. et al. Brucella modulates secretory trafficking via multiple type IV secretion effector proteins. PLoS Pathog. 9, e1003556 (2013). This paper identifies several novel T4SS effectors as well as a potential role for these effectors in induction of the UPR.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Salcedo, S. P. et al. BtpB, a novel Brucella TIR-containing effector protein with immune modulatory functions. Front. Cell. Infect. Microbiol. 3, 28 (2013).

    PubMed  PubMed Central  Google Scholar 

  62. de Jong, M. F. et al. Sensing of bacterial type IV secretion via the unfolded protein response. mBio 4, e00418-12 (2013). This paper shows that elements of the UPR sense localization of a Brucella spp. effector protein to the ER.

    PubMed  PubMed Central  Google Scholar 

  63. Barlowe, C. et al. COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum. Cell 77, 895–907 (1994).

    CAS  PubMed  Google Scholar 

  64. Kuge, O. et al. SAR1 promotes vesicle budding from the endoplasmic reticulum but not Golgi compartments. J. Cell Biol. 125, 51–65 (1994).

    CAS  PubMed  Google Scholar 

  65. Fugier, E. et al. The glyceraldehyde-3-phosphate dehydrogenase and the small GTPase Rab 2 are crucial for Brucella replication. PLoS Pathog. 5, e1000487 (2009).

    PubMed  PubMed Central  Google Scholar 

  66. Seimon, T. A. et al. Induction of ER stress in macrophages of tuberculosis granulomas. PLoS ONE 5, e12772 (2010).

    PubMed  PubMed Central  Google Scholar 

  67. Baird, M. et al. The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner. Lab. Invest. 93, 112–122 (2012).

    PubMed  Google Scholar 

  68. Akazawa, Y. et al. Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis. PLoS ONE 8, e82322 (2013).

    PubMed  PubMed Central  Google Scholar 

  69. Smith, J. A. et al. Brucella induces an unfolded protein response via TcpB that supports intracellular replication in macrophages. PLoS Pathog. 9, e1003785 (2013). This paper implicates a bacterial TIR domain-containing protein in induction of the UPR in B. abortus -infected macrophages.

    PubMed  PubMed Central  Google Scholar 

  70. Pillich, H., Loose, M., Zimmer, K.-P. & Chakraborty, T. Activation of the unfolded protein response by Listeria monocytogenes. Cell. Microbiol. 14, 949–964 (2012).

    CAS  PubMed  Google Scholar 

  71. Qin, Q. M. et al. RNAi screen of endoplasmic reticulum-associated host factors reveals a role for IRE1α in supporting Brucella replication. PLoS Pathog. 4, e1000110 (2008). This paper is the first to report a UPR-associated factor in promoting bacterial replication.

    PubMed  PubMed Central  Google Scholar 

  72. Gekara, N. O., Groebe, L., Viegas, N. & Weiss, S. Listeria monocytogenes desensitizes immune cells to subsequent Ca2+ signaling via listeriolysin O-induced depletion of intracellular Ca2+ stores. Infect. Immun. 76, 857–862 (2008).

    CAS  PubMed  Google Scholar 

  73. Price, C. T., Al-Quadan, T., Santic, M., Rosenshine, I. & Abu Kwaik, Y. Host proteasomal degradation generates amino acids essential for intracellular bacterial growth. Science 334, 1553–1557 (2011).

    CAS  PubMed  Google Scholar 

  74. Bischof, L. J. et al. Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo. PLoS Pathog. 4, e1000176 (2008). This paper shows that the UPR functions as a defence mechanism against the action of bacterial pore-forming toxins.

    PubMed  PubMed Central  Google Scholar 

  75. Morinaga, N., Yahiro, K., Matsuura, G., Moss, J. & Noda, M. Subtilase cytotoxin, produced by Shiga-toxigenic Escherichia coli, transiently inhibits protein synthesis of Vero cells via degradation of BiP and induces cell cycle arrest at G1 by downregulation of cyclin D1. Cell. Microbiol. 10, 921–929 (2008).

    CAS  PubMed  Google Scholar 

  76. Paton, A. W. et al. AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature 443, 548–552 (2006). This paper shows that a toxin of enterohaemorrhagic E. coli can cleave BiP.

    CAS  PubMed  Google Scholar 

  77. Wolfson, J. J. et al. Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways. Cell. Microbiol. 10, 1775–1786 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chaudhary, A. et al. The Brucella TIR-like protein TcpB interacts with the death domain of MyD88. Biochem. Biophys. Res. Commun. 417, 299–304 (2012).

    CAS  PubMed  Google Scholar 

  79. Cirl, C. et al. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nature Med. 14, 399–406 (2008).

    CAS  PubMed  Google Scholar 

  80. Radhakrishnan, G. K., Harms, J. S. & Splitter, G. A. Modulation of microtubule dynamics by a TIR domain protein from the intracellular pathogen Brucella melitensis. Biochem. J. 439, 79–83 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sengupta, D. et al. Subversion of innate immune responses by Brucella through the targeted degradation of the TLR signaling adapter, MAL. J. Immunol. 184, 956–964 (2010).

    CAS  PubMed  Google Scholar 

  82. Snyder, G. A. et al. Crystal structures of the Toll/interleukin-1 receptor (TIR) domains from the Brucella protein TcpB and host adaptor TIRAP reveal mechanisms of molecular mimicry. J. Biol. Chem. 289, 669–679 (2014).

    CAS  PubMed  Google Scholar 

  83. Salcedo, S. P. et al. Brucella control of dendritic cell maturation is dependent on the TIR-containing protein btp1. PLoS Pathog. 4, e21 (2008).

    PubMed  PubMed Central  Google Scholar 

  84. Hasnain, S. Z., Lourie, R., Das, I., Chen, A. C. & McGuckin, M. A. The interplay between endoplasmic reticulum stress and inflammation. Immunol. Cell Biol. 90, 260–270 (2012).

    CAS  PubMed  Google Scholar 

  85. Uehara, T. et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441, 513–517 (2006).

    CAS  PubMed  Google Scholar 

  86. Martinon, F., Chen, X., Lee, A. H. & Glimcher, L. H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nature Immunol. 11, 411–418 (2010).

    CAS  Google Scholar 

  87. Pahl, H. L. & Baeuerle, P. A. A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-κB. EMBO J. 14, 2580–2588 (1995). This paper provides the first evidence of a link between ER stress and NF-κB signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Pahl, H. L. & Baeuerle, P. A. Expression of influenza virus hemagglutinin activates transcription factor NF-κB. J. Virol. 69, 1480–1484 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Malathi, K., Dong, B., Gale, M. Jr & Silverman, R. H. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448, 816–819 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Malathi, K. et al. RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP. RNA 16, 2108–2119 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunol. 5, 730–737 (2004).

    CAS  Google Scholar 

  92. Zeng, L. et al. XBP-1 couples endoplasmic reticulum stress to augmented IFN-ß induction via a cis-acting enhancer in macrophages. J. Immunol. 185, 2324–2330 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lerner, A. G. et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell. Metab. 16, 250–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Menu, P. et al. ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis. 3, e261 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell. Metab. 16, 265–273 (2012). References 93–95 demonstrate a link between ER stress and activation of the NLRP3 inflammasome.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yamazaki, H. et al. Activation of the Akt–NF-κB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response. J. Immunol. 183, 1480–1487 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Vecchi, C. et al. ER stress controls iron metabolism through induction of hepcidin. Science 325, 877–880 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang, K. et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124, 587–599 (2006).

    CAS  PubMed  Google Scholar 

  99. Barquero-Calvo, E. et al. Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection. PLoS ONE 2, e631 (2007).

    PubMed  PubMed Central  Google Scholar 

  100. Lapaque, N. et al. Differential inductions of TNF-α and IGTP, IIGP by structurally diverse classic and non-classic lipopolysaccharides. Cell. Microbiol. 8, 401–413 (2006).

    CAS  PubMed  Google Scholar 

  101. Roux, C. M. et al. Brucella requires a functional type IV secretion system to elicit innate immune responses in mice. Cell. Microbiol. 9, 1851–1869 (2007).

    CAS  PubMed  Google Scholar 

  102. Chang, W. L. et al. Influenza virus infection causes global respiratory tract B cell response modulation via innate immune signals. J. Immunol. 178, 1457–1467 (2007).

    CAS  PubMed  Google Scholar 

  103. Lee, S. Y., Lee, M. S., Cherla, R. P. & Tesh, V. L. Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells. Cell. Microbiol. 10, 770–780 (2008).

    CAS  PubMed  Google Scholar 

  104. Lee, M. S., Kim, M. H. & Tesh, V. L. Shiga toxins expressed by human pathogenic bacteria induce immune responses in host cells. J. Microbiol. 51, 724–730 (2013).

    CAS  PubMed  Google Scholar 

  105. Heyderman, R. S., Soriani, M. & Hirst, T. R. Is immune cell activation the missing link in the pathogenesis of post-diarrhoeal HUS? Trends Microbiol. 9, 262–266 (2001).

    CAS  PubMed  Google Scholar 

  106. Zhao, Y. et al. Subtilase cytotoxin activates MAP kinases through PERK and IRE1 branches of the unfolded protein response. Toxicol. Sci. 120, 79–86 (2011).

    CAS  PubMed  Google Scholar 

  107. Harama, D. et al. A subcytotoxic dose of subtilase cytotoxin prevents lipopolysaccharide-induced inflammatory responses, depending on its capacity to induce the unfolded protein response. J. Immunol. 183, 1368–1374 (2009).

    CAS  PubMed  Google Scholar 

  108. Mimura, N. et al. Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma. Blood 119, 5772–5781 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Watowich, S. S., Morimoto, R. I. & Lamb, R. A. Flux of the paramyxovirus hemagglutinin-neuraminidase glycoprotein through the endoplasmic reticulum activates transcription of the GRP78-BiP gene. J. Virol. 65, 3590–3597 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Isler, J. A., Skalet, A. H. & Alwine, J. C. Human cytomegalovirus infection activates and regulates the unfolded protein response. J. Virol. 79, 6890–6899 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Stahl, S. et al. Cytomegalovirus downregulates IRE1 to repress the unfolded protein response. PLoS Pathog. 9, e1003544 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Tirosh, B. et al. Human cytomegalovirus protein US11 provokes an unfolded protein response that may facilitate the degradation of class I major histocompatibility complex products. J. Virol. 79, 2768–2779 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Tardif, K. D., Mori, K., Kaufman, R. J. & Siddiqui, A. Hepatitis C virus suppresses the IRE1–XBP1 pathway of the unfolded protein response. J. Biol. Chem. 279, 17158–17164 (2004).

    CAS  PubMed  Google Scholar 

  114. Chan, S. W. Unfolded protein response in hepatitis C virus infection. Front. Microbiol. 5, 233 (2014).

    PubMed  PubMed Central  Google Scholar 

  115. Trujillo-Alonso, V., Maruri-Avidal, L., Arias, C. F. & Lopez, S. Rotavirus infection induces the unfolded protein response of the cell and controls it through the nonstructural protein NSP3. J. Virol. 85, 12594–12604 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Zambrano, J. L. et al. Rotavirus infection activates the UPR but modulates its activity. Virol. J. 8, 359 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Smith, J. A. A new paradigm: innate immune sensing of viruses via the unfolded protein response. Front. Microbiol. 5, 222 (2014).

    PubMed  PubMed Central  Google Scholar 

  118. Fronzes, R., Christie, P. J. & Waksman, G. The structural biology of type IV secretion systems. Nature Rev. Microbiol. 7, 703–714 (2009).

    CAS  Google Scholar 

  119. Juhas, M., Crook, D. W. & Hood, D. W. Type IV secretion systems: tools of bacterial horizontal gene transfer and virulence. Cell. Microbiol. 10, 2377–2386 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Nagai, H. & Kubori, T. Type IVB secretion systems of Legionella and other Gram-negative bacteria. Front. Microbiol. 2, 136 (2011).

    PubMed  PubMed Central  Google Scholar 

  121. de Jong, M. F. & Tsolis, R. M. Brucellosis and type IV secretion. Future Microbiol. 7, 47–58 (2012).

    PubMed  Google Scholar 

  122. Voth, D. E., Broederdorf, L. J. & Graham, J. G. Bacterial type IV secretion systems: versatile virulence machines. Future Microbiol. 7, 241–257 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Goldszmid, R. S. et al. Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells. J. Exp. Med. 206, 399–410 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Sinai, A. P., Webster, P. & Joiner, K. A. Association of host cell endoplasmic reticulum and mitochondria with the Toxoplasma gondii parasitophorous vacuole membrane: a high affinity interaction. J. Cell Sci. 110, 2117–2128 (1997).

    CAS  PubMed  Google Scholar 

  125. Wang, T. et al. Toxoplasma gondii induce apoptosis of neural stem cells via endoplasmic reticulum stress pathway. Parasitology 141, 988–995 (2014).

    CAS  PubMed  Google Scholar 

  126. Xu, X. et al. Reactive oxygen species-triggered trophoblast apoptosis is initiated by endoplasmic reticulum stress via activation of caspase-12, CHOP, and the JNK pathway in Toxoplasma gondii infection in mice. Infect. Immun. 80, 2121–2132 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Yamamoto, M. et al. ATF6ß is a host cellular target of the Toxoplasma gondii virulence factor ROP18. J. Exp. Med. 208, 1533–1546 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Washington State University funds and Public Health Service (PHS) grant AI112649 to J.C., and PHS grants AIAI050553, AI097107 and AI090387 to R.M.T.

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Authors and Affiliations

  1. Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman, 99164, Washington, USA

    Jean Celli

  2. Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, 95616, California, USA

    Renée M. Tsolis

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  1. Jean Celli
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Correspondence to Jean Celli or Renée M. Tsolis.

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PowerPoint slides

Glossary

Lysosomes

Membrane-enclosed organelles of eukaryotic cells that contain acid hydrolases capable of degrading biological polymers.

Secretory pathway

A series of intracellular steps that eukaryotic cells use to transport proteins to specific cellular locations and also for extracellular secretion, which involves the endoplasmic reticulum and Golgi apparatus.

Endocytic pathway

An array of intracellular membrane-bound compartments (including early endosomes, late endosomes and lysosomes) that internalize molecules at the plasma membrane and sort them for either degradation or recycling back to the plasma membrane.

Autophagic pathway

A series of processes of recognition, capture and degradation of cytosolic content, such as protein aggregates, damaged organelles and invading microbes, which occur via engulfment into double-membrane bound autophagosomes and maturation along the endocytic pathway into degradative autolysosomes.

ER-associated degradation

(ERAD). An essential component of endoplasmic reticulum (ER) quality control, the ERAD is a process of removal of misfolded or misassembled proteins in the lumen or membranes of the ER via polyubiquitination and targeting to the proteasome for degradation.

Programmed cell death

A genetically regulated process of cellular suicide that involves specialized intracellular machineries and enables the elimination of specific cells.

Retrotranslocation

The process by which the transport of misfolded proteins are transported from the endoplasmic reticulum lumen to the cytosol for degradation by the proteasome.

Polyubiquitination

A post-translational modification of proteins that includes the covalent addition of chains of ubiquitin monomers that function as signals for proteasomal degradation of misfolded proteins.

Proteasome

A large protein complex that degrades unneeded or misfolded proteins that have been tagged via polyubiquitination.

SNARE proteins

(Soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins). Proteins that are involved in mediating intracellular membrane vesicle fusion in eukaryotic cells.

Thioredoxin-interacting protein

(TXNIP). A protein that is induced via protein kinase R (PKR)-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1), and that activates inflammatory processes and cell death following unabated endoplasmic reticulum stress.

Hepcidin

A hormone that regulates iron homeostasis in mammals; it has a role in innate immunity as it limits iron availability to bacteria.

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Celli, J., Tsolis, R. Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?. Nat Rev Microbiol 13, 71–82 (2015). https://doi.org/10.1038/nrmicro3393

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