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

Authors
  • Mendez, Jonathan M1
  • Kolora, Lakshmi Divya1
  • Lemon, James S1
  • Dupree, Steven L1
  • Keestra-Gounder, A Marijke2
  • 1 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • 2 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA [email protected]
Type
Published Article
Journal
Infection and Immunity
Publisher
American Society for Microbiology
Publication Date
Aug 01, 2019
Volume
87
Issue
8
Identifiers
DOI: 10.1128/IAI.00826-18
PMID: 31109951
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2019 Mendez et al.

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