Activation of cell stress response pathways by Shiga toxins - PubMed (original) (raw)

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Activation of cell stress response pathways by Shiga toxins

Vernon L Tesh. Cell Microbiol. 2012 Jan.

Abstract

Shiga toxin-producing bacteria cause widespread outbreaks of bloody diarrhoea that may progress to life-threatening systemic complications. Shiga toxins (Stxs), the main virulence factors expressed by the pathogens, are ribosome-inactivating proteins which inhibit protein synthesis by removing an adenine residue from 28S rRNA. Recently, Stxs were shown to activate multiple stress-associated signalling pathways in mammalian cells. The ribotoxic stress response is activated following the depurination reaction localized to the α-sarcin/ricin loop of eukaryotic ribosomes. The unfolded protein response (UPR) may be initiated by toxin unfolding within the endoplasmic reticulum, and maintained by production of truncated, misfolded proteins following intoxication. Activation of the ribotoxic stress response leads to signalling through MAPK cascades, which appears to be critical for activation of innate immunity and regulation of apoptosis. Precise mechanisms linking ribosomal damage with MAPK activation require clarification but may involve recognition of ribosomal conformational changes and binding of protein kinases to ribosomes, which activate MAP3Ks and MAP2Ks. Stxs appear capable of activating all ER membrane localized UPR sensors. Prolonged signalling through the UPR induces apoptosis in some cell types. The characterization of stress responses activated by Stxs may identify targets for the development of interventional therapies to block cell damage and disease progression.

© 2011 Blackwell Publishing Ltd.

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Figures

Fig. 1

Fig. 1. Induction of the ribotoxic stress response by Stxs

Following retrotranslocation of Stx A1-fragment (green circle) across the ER membrane, the depurination reaction involving a single adenine residue within the α-sarcin/ricin loop of the 28S rRNA ribosomal subunit (blue circles) may induce a sufficient conformational change to allow the serine/threonine protein kinase PKR to bind. Additional kinases may also recognize changes in ribosomal tertiary structure. Stxs appear to be capable of activating all three MAPKs: JNK1,2, the p38 MAPK isoforms, and ERK1,2. Upstream molecules transducing signals from intoxicated ribosomes to activate MAPKs remain to be fully characterized, but include the MAP3Ks, ASK-1 and ZAK, and the MAP2Ks, SEK1/MKK4 and MKK3/6. Downstream signaling molecules activated by the MAPKs regulate cytokine/chemokine gene expression at transcriptional and post-transcriptional levels, and activate apoptosis and cell survival pathways. Dual specificity phosphatases (DUSPs) are also activated by the ribotoxic stress response, suggesting that signals to ultimately down-regulate the response are initiated following intoxication.

Fig. 2

Fig. 2. Prolonged activation of the UPR by Stxs leads to apoptosis

Unfolded Stx A1-fragments and/or the presence of truncated, misfolded proteins within the ER of intoxicated monocytic THP-1 cells leads to increased phosphorylation of ER stress sensors PERK and IRE1, and cleavage of the sensor ATF6 from the 90 kDa precursor form to the active 50 kDa transcription factor. Expression of the transcription factor CHOP is up-regulated, which in turn, down-regulates expression of the anti-apoptotic factor Bcl-2, and up-regulates expression of the apoptosis inducing factor TRAIL and its receptor DR5. Release of Ca2+ from ER stores also activates calpains which may directly cleave procaspase-8. Reproduced from Lee et al., Cellular Microbiology 10(3):770–780 [2008] with permission of the authors and Wiley-Blackwell Publishers.

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References

    1. Alisi A, Spaziani A, Anticoli S, Ghidinelli M, Balsano C. PKR is a novel functional direct player that coordinates skeletal muscle differentiation via p38MAPK/AKT pathways. Cell Signal. 2008;20:534–542. - PubMed
    1. Allison HE. Stx-phages: drivers and mediators of the evolution of STEC and STEC-like pathogens. Future Microbiol. 2007;2:165–174. - PubMed
    1. Bae H, Gray JS, Li M, Vines L, Kim J, Pestka JJ. Hematopoietic cell kinase associates with the 40S ribosomal subunit and mediates the ribotoxic stress response to deoxynivalenol in mononuclear phagocytes. Toxicol Sci. 2010;115:444–452. - PMC - PubMed
    1. Bernales S, Papa FR, Walter P. Intracellular signaling by the unfolded protein response. Annu Rev Cell Dev Biol. 2006;22:487–508. - PubMed
    1. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–332. - PubMed

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