Manipulation of noncanonical Ire1-dependent MAPK signaling by a Vibrio agonist-antagonist effector pair
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ABSTRACT:
PROVIDER: PRJNA492339 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7885630.fastq.gz | Fastqsanger.gz | |||
| SRR7885621.fastq.gz | Fastqsanger.gz | |||
| SRR7885631.fastq.gz | Fastqsanger.gz | |||
| SRR7885622.fastq.gz | Fastqsanger.gz | |||
| SRR7885632.fastq.gz | Fastqsanger.gz |
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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
2021-01-28 | GSE120273 | GEO
Project description:Diverse bacterial pathogens employ effector delivery systems to disrupt vital cellular processes in the host (N. M. Alto and K. Orth, Cold Spring Harbor Perspect Biol 4:a006114, 2012, https://doi.org/10.1101/cshperspect.a006114). The type III secretion system 1 of the marine pathogen Vibrio parahaemolyticus utilizes the sequential action of four effectors to induce a rapid, proinflammatory cell death uniquely characterized by a prosurvival host transcriptional response (D. L. Burdette, M. L. Yarbrough, A Orvedahl, C. J. Gilpin, and K. Orth, Proc Natl Acad Sci USA 105:12497-12502, 2008, https://doi.org/10.1073/pnas.0802773105; N. J. De Nisco, M. Kanchwala, P. Li, J. Fernandez, C. Xing, and K. Orth, Sci Signal 10:eaa14501, 2017, https://doi.org/10.1126/scisignal.aal4501). Herein, we show that this prosurvival response is caused by the action of the channel-forming effector VopQ that targets the host V-ATPase, resulting in lysosomal deacidification and inhibition of lysosome-autophagosome fusion. Recent structural studies have shown how VopQ interacts with the V-ATPase and, while in the ER, a V-ATPase assembly intermediate can interact with VopQ, causing a disruption in membrane integrity. Additionally, we observed that VopQ-mediated disruption of the V-ATPase activates the IRE1 branch of the unfolded protein response (UPR), resulting in an IRE1-dependent activation of ERK1/2 MAPK signaling. We also find that this early VopQ-dependent induction of ERK1/2 phosphorylation is terminated by the VopS-mediated inhibitory AMPylation of Rho GTPase signaling. Since VopS dampens VopQ-induced IRE1-dependent ERK1/2 activation, we propose that IRE1 activates ERK1/2 phosphorylation at or above the level of Rho GTPases. This study illustrates how temporally induced effectors can work as in tandem as agonist/antagonist to manipulate host signaling and reveals new connections between V-ATPase function, UPR, and MAPK signaling.IMPORTANCE Vibrio parahaemolyticus is a seafood-borne pathogen that encodes two type 3 secretion systems (T3SS). The first system, T3SS1, is thought to be maintained in all strains of V. parahaemolyticus to maintain survival in the environment, whereas the second system, T3SS2, is linked to clinical isolates and disease in humans. Here, we found that first system targets evolutionarily conserved signaling systems to manipulate host cells, eventually causing a rapid, orchestrated cells death within 3 h. We have found that the T3SS1 injects virulence factors that temporally manipulate host signaling. Within the first hour of infection, the effector VopQ acts first by activating host survival signals while diminishing the host cell apoptotic machinery. Less than an hour later, another effector, VopS, reverses activation and inhibition of these signaling systems, ultimately leading to death of the host cell. This work provides example of how pathogens have evolved to manipulate the interplay between T3SS effectors to regulate host signaling pathways.
| S-EPMC7883537 | biostudies-literature
Project description:Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1-alpha promotes cancer cell survival
| PRJNA717050 | ENA
Project description:Eukaryotic IRE1 mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, mammalian RIDD seemingly targets only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human breast cancer cells, we discovered not only canonical endomotif-containing RIDD substrates, but also many targets lacking recognizable motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displayed two basic endoribonuclease modalities: endomotif-specific cleavage, minimally requiring dimers; and endomotif-independent promiscuous processing, requiring phospho-oligomers. An oligomer-deficient mutant that did not support RIDDLE failed to rescue cancer-cell viability. These results link IRE1α oligomers, RIDDLE, and cell survival, advancing mechanistic understanding of the UPR.
2021-06-01 | GSE169584 | GEO
Project description:Eukaryotic IRE1 mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, mammalian RIDD seemingly targets only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human breast cancer cells, we discovered not only canonical endomotif-containing RIDD substrates, but also many targets lacking recognizable motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displayed two basic endoribonuclease modalities: endomotif-specific cleavage, minimally requiring dimers; and endomotif-independent promiscuous processing, requiring phospho-oligomers. An oligomer-deficient mutant that did not support RIDDLE failed to rescue cancer-cell viability. These results link IRE1α oligomers, RIDDLE, and cell survival, advancing mechanistic understanding of the UPR.
2021-06-01 | GSE169583 | GEO
Project description:Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1-alpha promotes cancer cell survival [RNA-seq]
| PRJNA717051 | ENA
Project description:Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1-alpha promotes cancer cell survival [GRO-seq]
| PRJNA717052 | ENA
Project description:We investigate the contribution of IRE1 signaling to the modulation of U87 glioma cells transcriptome upon various stresses. To this end, IRE1 control and IRE1 dominant negative expressing U87 glioma cells were subjected to environmental or chemical challenges and their transcriptome monitored using Affymetrix microarrays. Stress-induced transcriptome modulation in function of IRE1 proficiency/deficiency
2011-12-31 | E-GEOD-27306 | biostudies-arrayexpress