Activation of the Unfolded Protein Response Is Required for Defenses against Bacterial Pore-Forming Toxin In Vivo

Bischof, Larry J.; Kao, Cheng–Yuan; Los, Ferdinand C. O.; Gonzalez, Manuel R.; Shen, Zhouxin; Briggs, Steven P.; Goot, F. Gisou van der; Aroian, Raffi V.

doi:10.1371/journal.ppat.1000176

Cited by 173 publications

(232 citation statements)

References 43 publications

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“…Endoplasmic reticulum (ER) stress pathways are central for host survival against PFTs, including LLO, and ER distribution is often altered during intoxication [10,11]. Concurrently, we have shown that Lm infection redistributes the ER chaperone Gp96 to the PM through an uncharacterized mechanism [12].…”

Section: Introductionmentioning

confidence: 83%

Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore‐forming toxins

et al. 2016

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During infection, plasma membrane (PM) blebs protect host cells against bacterial pore-forming toxins (PFTs), but were also proposed to promote pathogen dissemination. However, the details and impact of blebbing regulation during infection remained unclear. Here, we identify the endoplasmic reticulum chaperone Gp96 as a novel regulator of PFT-induced blebbing. Gp96 interacts with non-muscle myosin heavy chain IIA (NMHCIIA) and controls its activity and remodelling, which is required for appropriate coordination of bleb formation and retraction. This mechanism involves NMHCIIA-Gp96 interaction and their recruitment to PM blebs and strongly resembles retraction of uropod-like structures from polarized migrating cells, a process that also promotes NMHCIIA-Gp96 association. Consistently, Gp96 and NMHCIIA not only protect the PM integrity from listeriolysin O (LLO) during infection by Listeria monocytogenes but also affect cytoskeletal organization and cell migration. Finally, we validate the association between Gp96 and NMHCIIA in vivo and show that Gp96 is required to protect hosts from LLO-dependent killing.

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Section: Introductionmentioning

confidence: 83%

Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore‐forming toxins

et al. 2016

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“…the cell membrane such as that caused by a poreforming toxin, which activates the unfolded protein response downstream of PMK-1 (Bischof et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Anoxic Death in Caenorhabditis elegans by Mammalian Apoptosis Signal-Regulating Kinase (ASK) Family Proteins

et al. 2011

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Cells and organisms face anoxia in a wide variety of contexts, including ischemia and hibernation. Cells respond to anoxic conditions through multiple signaling pathways. We report that NSY-1, the Caenorhabditis elegans ortholog of mammalian apoptosis signal-regulating kinase (ASK) family of MAP kinase (MAPK) kinase kinases (MAP3Ks), regulates viability of animals in anoxia. Loss-of-function mutations of nsy-1 increased survival under anoxic conditions, and increased survival was also observed in animals with mutations in tir-1 and the MAPK kinase (MAP2K) sek-1, which are upstream and downstream factors of NSY-1, respectively. Consistent with these findings, anoxia was found to activate the p38 MAPK ortholog PMK-1, and this was suppressed in nsy-1 and tir-1 mutant animals. Furthermore, double-mutant analysis showed that the insulin-signaling pathway, which also regulates viability in anoxia, functioned in parallel to NSY-1. These results suggest that the TIR-1-NSY-1-SEK-1-PMK-1 pathway plays important roles in the reponse to anoxia in C. elegans.

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“…To overcome this limit, a new collision-activated fragmentation technique, called PQD, was invented that enables routine and reliable measurement of ions down to 50 m/z (18). We have developed and successfully applied a combined CID-PQD scan approach for peptide identification and quantitation (19,20).…”

Section: Fig 1 Overview Of Experimental Design and Sample Collectionmentioning

confidence: 99%

Quantitative Proteome Analysis of Pluripotent Cells by iTRAQ Mass Tagging Reveals Post-transcriptional Regulation of Proteins Required for ES Cell Self-renewal

O’Brien¹,

Shen²,

Tachikawa³

et al. 2010

Molecular & Cellular Proteomics

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Embryonic stem cells and embryonal carcinoma cells share two key characteristics: pluripotency (the ability to differentiate into endoderm, ectoderm, and mesoderm) and self-renewal (the ability to grow without change in an untransformed, euploid state). Much has been done to identify and characterize transcription factors that are necessary or sufficient to maintain these characteristics. Oct-4 and Nanog are necessary to maintain pluripotency; they are down-regulated at the mRNA level by differentiation. There may be additional regulatory genes whose mRNA levels are unchanged but whose proteins are destabilized during differentiation. We generated proteome-wide, quantitative profiles of ES and embryonal carcinoma cells during differentiation, replicating a microarray-based study by Aiba et al. We identified several proteins whose levels decreased during differentiation in both cell types but whose mRNA levels were unchanged. We confirmed several of these cases by RT-PCR and Western blot. Racgap1 (also known as mgcRacgap) was particularly interesting because it is required for viability of preimplantation embryos and hematopoietic stem cells, and it is also required for differentiation. To confirm our observation that RACGAP-1 declines during retinoic acid-mediated differentiation, we used multiple reaction monitoring, a targeted mass spectrometry-based quantitation method, and determined that RACGAP-1 levels decline by half during retinoic acid-mediated differentiation. We knocked down Racgap-1 mRNA levels using a panel of five shRNAs. This resulted in a loss of self-renewal that correlated with the level of knockdown. We conclude that RACGAP-1 is post-transcriptionally regulated during blastocyst development to enable differentiation by inhibiting ES cell self-renewal. Molecular & Cellular Proteomics 9: 2238 -2251, 2010.

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Activation of the Unfolded Protein Response Is Required for Defenses against Bacterial Pore-Forming Toxin In Vivo

Cited by 173 publications

References 43 publications

Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore‐forming toxins

Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore‐forming toxins

Regulation of Anoxic Death in Caenorhabditis elegans by Mammalian Apoptosis Signal-Regulating Kinase (ASK) Family Proteins

Quantitative Proteome Analysis of Pluripotent Cells by iTRAQ Mass Tagging Reveals Post-transcriptional Regulation of Proteins Required for ES Cell Self-renewal

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