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Coupling ER stress to STAT1-mediated immunity against bacterial infection

ABSTRACT: Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are hallmarks of pathogen infection. The UPR drives pro-inflammatory responses to ER stress but its role in interferon signaling is unknown. Using metabolomics approaches, we observed that pharmacological ER stress reprogrammed macrophage metabolism to a pro-inflammatory “M1-like” phenotype and enhanced the microbicidal activity of these cells to restrict bacterial infection. Phospho-proteomics analysis showed that this anti-microbial response was mediated via the UPR serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1) and activation of signal transducer and transcription activator 1 (STAT1) required for interferon signaling. We also demonstrated that blockade of IRE1 signaling by the bacterial pathogen Legionella pneumophila inhibited STAT1-mediated immune responses to infection. These findings reveal the potential for ER stress to initiate anti-microbial STAT1 signaling in the absence of other pro-inflammatory stimuli and how this response is inhibited by a bacterial pathogen during infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287755 | GEO | 2025/03/31

REPOSITORIES: GEO

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Project description:Abstract: Many bacterial pathogens employ effector delivery systems to disrupt vital cellular processes in the host. The type III secretion system 1 of the marine pathogen, Vibrio parahaemolyticus, utilizes the sequential action of four effectors to induce a rapid, pro-inflammatory cell death uniquely characterized by a pro-survival host transcriptional response. Herein we show that this pro-survival response is due to the action of the channel-forming effector VopQ that disrupts autophagic flux through two activities: lysosomal deacidification and inhibition of lysosome-autophagosome fusion. Using a point mutation to separate these two functions, we demonstrate that VopQ acts as an agonist of host ERK1/2 MAPK signaling as a result of its fusion-blocking activity. The pulse of ERK1/2 phosphorylation is restricted to early infection by the timed inhibition of Rho GTPase signaling by the antagonist effector VopS. Inhibition of autophagosome-lysosome fusion and activation of MAPK kinase signaling can be linked to the UPR. VopQ not only activates the IRE1 branch of the UPR, but VopQ’s activation of ERK1/2 MAPK signaling is dependent on IRE1. Since VopS can dampen VopQ-induced IRE1-dependent ERK1/2 activation, we suggest that IRE1 must activate ERK1/2 signaling at or above the level of Rho GTPases. This work elucidates new connections between host autophagy, MAPK signaling and the UPR that bacterial pathogens have evolved to manipulate the host. Methods: We employed genome-wide transcriptional profiling methods (RNA-seq) to measure changes in gene expression in response to infection with V. para T3SS1+, T3SS1+ ΔvopQ, or T3SS1+ ΔvopS. Time points were collected 90 minutes post-infection. In total, libraries from 12 samples (triplicates of uninfected, T3SS1+, T3SS1+ ΔvopQ, and T3SS1+ ΔvopS) were sequenced and mapped to the human genome. EdgeR was used for differential expression analysis using statistical cutoffs of of false discovery rate (FDR) ≤0.01, log2counts-per-million (log2CPM) ≥0 and fold change (FC) cutoffs of -1.5≥ FC ≥1.5

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Coupling ER stress to STAT1-mediated immunity against bacterial infection

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