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Induction of endoplasmic reticulum stress and unfolded protein response constitutes a pathogenic strategy of group A streptococcus.

Baruch M, Hertzog BB, Ravins M, Anand A, Cheng CY, Biswas D, Tirosh B, Hanski E - Front Cell Infect Microbiol (2014)

Bottom Line: In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host.GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS).GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Hebrew University of Jerusalem (HUJI) Jerusalem, Israel.

ABSTRACT
The connection between bacterial pathogens and unfolded protein response (UPR) is poorly explored. In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host. GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS). By poorly understood pathways, these toxins trigger UPR leading to the induction of the transcriptional regulator ATF4 and consequently to the upregulation of asparagine synthetase (ASNS) transcription leading to production and release of ASN. GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication. We suggest that induction of UPR by GAS and by other bacterial pathogens represent means through which bacterial pathogens gain nutrients from the host, obviating the need to become internalized or inflict irreversible cell damage.

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ER stress and UPR. Upper panel—the three transmembrane receptor proteins that are responsible for triggering UPR in cells experiencing ER stress. Lower panel—induction of asns transcription through the PERK/eIF2/ATF4 pathway. During UPR, PERK phosphorylates elf2α, which in turn elevates the translation of the transcription factor ATF4. ATF4 upregulates the transcription of several genes including that of asns.
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Figure 1: ER stress and UPR. Upper panel—the three transmembrane receptor proteins that are responsible for triggering UPR in cells experiencing ER stress. Lower panel—induction of asns transcription through the PERK/eIF2/ATF4 pathway. During UPR, PERK phosphorylates elf2α, which in turn elevates the translation of the transcription factor ATF4. ATF4 upregulates the transcription of several genes including that of asns.

Mentions: In mammalian cells UPR is mediated by three major signal transduction pathways: PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) (Figure 1). These signaling pathways are all initiated when misfolded proteins are sensed in the ER lumen. These three pathways combat ER stress through complementary strategies including: (a) attenuation of global protein translation to reduce the influx of client proteins into the ER; (b) up-regulation of chaperones and enzymes involved in refolding of misfolded proteins; and (c) enhancing ER-associated degradation (ERAD) to facilitate clearance of misfolded proteins from the ER (Schroder and Kaufman, 2005; Ron and Walter, 2007). As mentioned above, a variety of external stimuli have been shown to cause UPR. This includes abiotic stresses; pharmacological agents and toxins producing imbalance of ER calcium and redox; anti-inflammatory agents causing vigorous protein synthesis; energy deprivation, amino acids and ATP depletion, genetic mutations occurring in protein misfolding diseases and microbial pathogens (Schroder and Kaufman, 2005; Yoshida, 2007; Walter and Ron, 2011). Since there are several potential cross-talks between UPR and microbial sensing pathways that trigger immune responses (Hotamisligil, 2010; Hasnain et al., 2012; Hetz, 2012; Martinon, 2012; Claudio et al., 2013), investigators started to explore how microbial pathogens cope with UPR that they induce and whether or not they are able to exploit UPR for their own “benefit” (Roy et al., 2006).


Induction of endoplasmic reticulum stress and unfolded protein response constitutes a pathogenic strategy of group A streptococcus.

Baruch M, Hertzog BB, Ravins M, Anand A, Cheng CY, Biswas D, Tirosh B, Hanski E - Front Cell Infect Microbiol (2014)

ER stress and UPR. Upper panel—the three transmembrane receptor proteins that are responsible for triggering UPR in cells experiencing ER stress. Lower panel—induction of asns transcription through the PERK/eIF2/ATF4 pathway. During UPR, PERK phosphorylates elf2α, which in turn elevates the translation of the transcription factor ATF4. ATF4 upregulates the transcription of several genes including that of asns.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120759&req=5

Figure 1: ER stress and UPR. Upper panel—the three transmembrane receptor proteins that are responsible for triggering UPR in cells experiencing ER stress. Lower panel—induction of asns transcription through the PERK/eIF2/ATF4 pathway. During UPR, PERK phosphorylates elf2α, which in turn elevates the translation of the transcription factor ATF4. ATF4 upregulates the transcription of several genes including that of asns.
Mentions: In mammalian cells UPR is mediated by three major signal transduction pathways: PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) (Figure 1). These signaling pathways are all initiated when misfolded proteins are sensed in the ER lumen. These three pathways combat ER stress through complementary strategies including: (a) attenuation of global protein translation to reduce the influx of client proteins into the ER; (b) up-regulation of chaperones and enzymes involved in refolding of misfolded proteins; and (c) enhancing ER-associated degradation (ERAD) to facilitate clearance of misfolded proteins from the ER (Schroder and Kaufman, 2005; Ron and Walter, 2007). As mentioned above, a variety of external stimuli have been shown to cause UPR. This includes abiotic stresses; pharmacological agents and toxins producing imbalance of ER calcium and redox; anti-inflammatory agents causing vigorous protein synthesis; energy deprivation, amino acids and ATP depletion, genetic mutations occurring in protein misfolding diseases and microbial pathogens (Schroder and Kaufman, 2005; Yoshida, 2007; Walter and Ron, 2011). Since there are several potential cross-talks between UPR and microbial sensing pathways that trigger immune responses (Hotamisligil, 2010; Hasnain et al., 2012; Hetz, 2012; Martinon, 2012; Claudio et al., 2013), investigators started to explore how microbial pathogens cope with UPR that they induce and whether or not they are able to exploit UPR for their own “benefit” (Roy et al., 2006).

Bottom Line: In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host.GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS).GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Hebrew University of Jerusalem (HUJI) Jerusalem, Israel.

ABSTRACT
The connection between bacterial pathogens and unfolded protein response (UPR) is poorly explored. In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host. GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS). By poorly understood pathways, these toxins trigger UPR leading to the induction of the transcriptional regulator ATF4 and consequently to the upregulation of asparagine synthetase (ASNS) transcription leading to production and release of ASN. GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication. We suggest that induction of UPR by GAS and by other bacterial pathogens represent means through which bacterial pathogens gain nutrients from the host, obviating the need to become internalized or inflict irreversible cell damage.

Show MeSH
Related in: MedlinePlus