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A NODding acquaintance with ER stress

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Accumulation of unfolded or misfolded proteins in the lumen of the endoplasmatic reticulum (ER) results in ER stress and induces the unfolded protein response (UPR)... The UPR consists of distinct cellular processes, such as increased transcription of repair proteins and chaperones, cell death and the induction of an inflammatory response resulting in the expression of pro-inflammatory cytokines such as IL-6... The NOD1/2 inflammatory pathway, classically associated with intracellular sensing of bacterial peptidoglycan (PGN), was shown to be required for ER stress-induced cytokine production... Prolonged UPR is introduced above UPR activates three ER stress sensors: double-stranded RNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6) and the inositol requiring kinase 1α (IRE1α; Figure 1)... When misfolded proteins accumulate in the ER, PERK oligomerizes and activates the transcription factor C/EBP homologous protein, resulting in the activation of pro-apoptotic members of the Bcl2 family, such as Puma and Bim... On the other hand, IRE1α activation recruits TNF receptor-associated factor 2 (TRAF2), which results in the activation of the NF-κB and JNK pathways and in the production of inflammatory cytokines... In their recent work, the Bäumler and Tsolis groups showed that cells and mice deficient in the TRAF2–NOD1/2–RIPK2 axis are deficient in IRE1α-induced IL-6 production... Genetic loss of the pattern recognition receptors NOD1/2 or receptor interacting kinase 2 (RIPK2) resulted in reduced IL-6 production in vivo and in vitro upon treatment with the ER stress inducer thapsigargin... Loss of NOD1/2 or RIPK2 had the same effect as treatment with KIRA6, an allosteric kinase inhibitor of IRE1... B. abortus infection induces ER stress by injecting the virulence factor VceC into host cells, which translocates to the ER and disrupts its normal function... Infection of mice with B. abortus, but not with a vceC mutant strain, induced IRE1α-dependent IL-6 production, which was significantly reduced in NOD1/2-deficient mice or when mice were treated with the ER stress inhibitor TUDCA or with the IRE1α kinase inhibitor KIRA6... RIPK2 inhibitors have already shown promise in the treatment of experimental autoimmune encephalomyelitis (EAE), the murine model for MS... Whether this effect was because of inhibition of the ER stress response during EAE or the inhibition of PGN-induced RIPK2 activation remains to be determined.

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Schematic of findings and potential applications from Keestra-Gounders et al. ER-stress inducers used in the study of Keestra-Gounders and colleagues (black) and ER-stress-associated diseases (red) induce three ER-localized receptors. The activation of IRE1α, ATF6 and PERK results in transcriptional upregulation of the degradation machinery and chaperones to reduce the pressure on the ER. In addition, PERK induces cell death via transcriptional upregulation of C/EBP homologous protein (CHOP), and IRE1α oligomerization results in the recruitment of TRAF2, which activates the NOD1/2–RIPK2 pathway, resulting in activation of NF-κB and AP-1 and the transcription of inflammatory cytokines such as IL-6. This newly described pathway suggests that inhibition of the NOD–RIPK2 axis, for example by RIPK2 kinase inhibitors, might be a strategy to reduce inflammation in ER-stress-driven diseases.
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fig1: Schematic of findings and potential applications from Keestra-Gounders et al. ER-stress inducers used in the study of Keestra-Gounders and colleagues (black) and ER-stress-associated diseases (red) induce three ER-localized receptors. The activation of IRE1α, ATF6 and PERK results in transcriptional upregulation of the degradation machinery and chaperones to reduce the pressure on the ER. In addition, PERK induces cell death via transcriptional upregulation of C/EBP homologous protein (CHOP), and IRE1α oligomerization results in the recruitment of TRAF2, which activates the NOD1/2–RIPK2 pathway, resulting in activation of NF-κB and AP-1 and the transcription of inflammatory cytokines such as IL-6. This newly described pathway suggests that inhibition of the NOD–RIPK2 axis, for example by RIPK2 kinase inhibitors, might be a strategy to reduce inflammation in ER-stress-driven diseases.

Mentions: Unfolded or misfolded proteins are normally sensed by a robust quality-control system and, if they are unable to be corrected, sent for degradation using the introduced above ER-associated degradation pathway (ERAD). Prolonged UPR is introduced above UPR activates three ER stress sensors: double-stranded RNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6) and the inositol requiring kinase 1α (IRE1α; Figure 1). Activation of these sensors results in increased degradation of misfolded proteins and in the induction of transcription of ERAD components and protein-folding chaperones to reduce stress on the ER.


A NODding acquaintance with ER stress
Schematic of findings and potential applications from Keestra-Gounders et al. ER-stress inducers used in the study of Keestra-Gounders and colleagues (black) and ER-stress-associated diseases (red) induce three ER-localized receptors. The activation of IRE1α, ATF6 and PERK results in transcriptional upregulation of the degradation machinery and chaperones to reduce the pressure on the ER. In addition, PERK induces cell death via transcriptional upregulation of C/EBP homologous protein (CHOP), and IRE1α oligomerization results in the recruitment of TRAF2, which activates the NOD1/2–RIPK2 pathway, resulting in activation of NF-κB and AP-1 and the transcription of inflammatory cytokines such as IL-6. This newly described pathway suggests that inhibition of the NOD–RIPK2 axis, for example by RIPK2 kinase inhibitors, might be a strategy to reduce inflammation in ER-stress-driven diseases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979412&req=5

fig1: Schematic of findings and potential applications from Keestra-Gounders et al. ER-stress inducers used in the study of Keestra-Gounders and colleagues (black) and ER-stress-associated diseases (red) induce three ER-localized receptors. The activation of IRE1α, ATF6 and PERK results in transcriptional upregulation of the degradation machinery and chaperones to reduce the pressure on the ER. In addition, PERK induces cell death via transcriptional upregulation of C/EBP homologous protein (CHOP), and IRE1α oligomerization results in the recruitment of TRAF2, which activates the NOD1/2–RIPK2 pathway, resulting in activation of NF-κB and AP-1 and the transcription of inflammatory cytokines such as IL-6. This newly described pathway suggests that inhibition of the NOD–RIPK2 axis, for example by RIPK2 kinase inhibitors, might be a strategy to reduce inflammation in ER-stress-driven diseases.
Mentions: Unfolded or misfolded proteins are normally sensed by a robust quality-control system and, if they are unable to be corrected, sent for degradation using the introduced above ER-associated degradation pathway (ERAD). Prolonged UPR is introduced above UPR activates three ER stress sensors: double-stranded RNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6) and the inositol requiring kinase 1α (IRE1α; Figure 1). Activation of these sensors results in increased degradation of misfolded proteins and in the induction of transcription of ERAD components and protein-folding chaperones to reduce stress on the ER.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Accumulation of unfolded or misfolded proteins in the lumen of the endoplasmatic reticulum (ER) results in ER stress and induces the unfolded protein response (UPR)... The UPR consists of distinct cellular processes, such as increased transcription of repair proteins and chaperones, cell death and the induction of an inflammatory response resulting in the expression of pro-inflammatory cytokines such as IL-6... The NOD1/2 inflammatory pathway, classically associated with intracellular sensing of bacterial peptidoglycan (PGN), was shown to be required for ER stress-induced cytokine production... Prolonged UPR is introduced above UPR activates three ER stress sensors: double-stranded RNA-activated protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6) and the inositol requiring kinase 1α (IRE1α; Figure 1)... When misfolded proteins accumulate in the ER, PERK oligomerizes and activates the transcription factor C/EBP homologous protein, resulting in the activation of pro-apoptotic members of the Bcl2 family, such as Puma and Bim... On the other hand, IRE1α activation recruits TNF receptor-associated factor 2 (TRAF2), which results in the activation of the NF-κB and JNK pathways and in the production of inflammatory cytokines... In their recent work, the Bäumler and Tsolis groups showed that cells and mice deficient in the TRAF2–NOD1/2–RIPK2 axis are deficient in IRE1α-induced IL-6 production... Genetic loss of the pattern recognition receptors NOD1/2 or receptor interacting kinase 2 (RIPK2) resulted in reduced IL-6 production in vivo and in vitro upon treatment with the ER stress inducer thapsigargin... Loss of NOD1/2 or RIPK2 had the same effect as treatment with KIRA6, an allosteric kinase inhibitor of IRE1... B. abortus infection induces ER stress by injecting the virulence factor VceC into host cells, which translocates to the ER and disrupts its normal function... Infection of mice with B. abortus, but not with a vceC mutant strain, induced IRE1α-dependent IL-6 production, which was significantly reduced in NOD1/2-deficient mice or when mice were treated with the ER stress inhibitor TUDCA or with the IRE1α kinase inhibitor KIRA6... RIPK2 inhibitors have already shown promise in the treatment of experimental autoimmune encephalomyelitis (EAE), the murine model for MS... Whether this effect was because of inhibition of the ER stress response during EAE or the inhibition of PGN-induced RIPK2 activation remains to be determined.

No MeSH data available.


Related in: MedlinePlus