Activation of the Endoplasmic Reticulum Stress Response Impacts the NOD1 Signaling Pathway

Abstract

Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern recognition receptor (PRR) responsible for sensing bacterial peptidoglycan fragments. Stimulation of NOD1 leads to a robust innate immune response via activation of the major transcription factor NF-κB. In addition to peptidoglycan sensing, NOD1 and the closely related PRR NOD2 have been linked to inflammation by responding to the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). Here we show that differential ER stress induction renders cells more susceptible to Salmonella enterica serovar Typhimurium infection in a NOD1-dependent manner, measured by increased NF-κB activation and cytokine expression. In HeLa57A cells stably transfected with an NF-κB::luciferase reporter, we show that cells undergoing ER stress induced by thapsigargin display a significant increase in NF-κB activation in response to NOD1 stimulation by C12-iE-DAP (acylated derivative of the iE-DAP dipeptide [gamma-d-glutamyl-meso-diaminopimelic acid]) and the S. Typhimurium effector protein SopE. Tunicamycin-induced ER stress had no effect on NOD1-stimulated NF-κB activation. We further show that the mouse intestinal epithelial cell line MODE-K and RAW264.7 macrophages are more responsive to Salmonella infection when treated with thapsigargin but not with tunicamycin. These profound differences between thapsigargin- and tunicamycin-treated cells upon inflammation suggest that different components downstream of the UPR contribute to NOD1 activation. We found that the NOD1-induced inflammatory response is dependent on protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation in conjunction with stimulation of the inositol triphosphate receptor (IP3R). Together, these results suggest that differential UPR activation makes cells more responsive to bacterial infections in a NOD1-dependent manner.

NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice

“…First, the interaction between TNF-α and the TNF-α receptor or between IL-1β and the IL-1 receptor can trigger the activation of NF-κB [36,55], which contributes to the upregulation of NOD1 and its adaptor RIP2. Second, endoplasmic reticulum (ER) stress, which can be initiated in response to TNF-α/IL-1β [56,57], was recently reported to contribute to the interaction of tumour necrosis factor (TNF) receptorassociated factor 2 (TRAF2) with NOD1 and lead to NOD1 activation [58,59]. However, the underlying mechanism by which TNF-α/IL-1β induced NOD1 and RIP2 upregulation at the molecular level remains to be further explored.…”

Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy

“…However, TLR engagement in itself can trigger ER stress through activation of XBP1, essential for production of inflammatory cytokines in macrophages ( 48 ). HLA-B27 misfolding was associated with enhanced replication of Salmonella by the activation of the unfolded protein response (UPR), through the transcription factor XBP1 ( 49 ) Although this study employs HeLa cells that do not express TLR, it is possible that innate immune receptors may be involved in response to bacteria or bacterial products ( 50 ). In another study, peripheral blood and serum polymerase chain reaction (PCR) analysis in patients with Chlamydia induced ReA showed the presence of DNA from C. trachomatis in the peripheral blood cells, but not in the serum ( 51 ).…”

Innate Immune Receptors, Key Actors in Cardiovascular Diseases

“…The link between NOD1 and ER stress appears to be the unfolded protein response, as inhibiting IRE1α, a kinase implicated in this pathway, attenuates the NOD1-associated inflammatory reaction ( 170 ). Some studies have associated ER stress with an imbalance in cellular Ca 2+ and the activation of NOD1 signaling ( 171 , 172 ). A recent study revealed that NOD1 activation both by bacterial pathogens and the NOD ligand C12-iE-DAP induced unfolded protein response activation through the ER kinase PERK, as well as Ca 2+ flux from the ER membrane Ca 2+ channel IP3R, which exacerbated the inflammatory response via NOD1 signaling ( 171 ).…”

“…Some studies have associated ER stress with an imbalance in cellular Ca 2+ and the activation of NOD1 signaling ( 171 , 172 ). A recent study revealed that NOD1 activation both by bacterial pathogens and the NOD ligand C12-iE-DAP induced unfolded protein response activation through the ER kinase PERK, as well as Ca 2+ flux from the ER membrane Ca 2+ channel IP3R, which exacerbated the inflammatory response via NOD1 signaling ( 171 ). In the same line, Molinaro et al.…”