scholarly journals Non-canonical activation of the ER stress sensor ATF6 by Legionella pneumophila effectors

2021 ◽  
Vol 4 (12) ◽  
pp. e202101247
Author(s):  
Nnejiuwa U Ibe ◽  
Advait Subramanian ◽  
Shaeri Mukherjee
Keyword(s):  
Legionella Pneumophila ◽  
Nuclear Translocation ◽  
Bacterial Pathogen ◽  
Effector Proteins ◽  
Regulatory Control ◽  
Unfolded Protein ◽  
Bacterial Proteins ◽  
Protein Response ◽  
Upr Pathway ◽  
Target Gene Transcription

The intracellular bacterial pathogen Legionella pneumophila (L.p.) secretes ∼330 effector proteins into the host cell to sculpt an ER-derived replicative niche. We previously reported five L.p. effectors that inhibit IRE1, a key sensor of the homeostatic unfolded protein response (UPR) pathway. In this study, we discovered a subset of L.p. toxins that selectively activate the UPR sensor ATF6, resulting in its cleavage, nuclear translocation, and target gene transcription. In a deviation from the conventional model, this L.p.–dependent activation of ATF6 does not require its transport to the Golgi or its cleavage by the S1P/S2P proteases. We believe that our findings highlight the unique regulatory control that L.p. exerts upon the three UPR sensors and expand the repertoire of bacterial proteins that selectively perturb host homeostatic pathways.

scholarly journals Non-canonical activation of the ER stress sensor ATF6 by Legionella pneumophila effectors

2020 ◽  
Author(s):  
Nnejiuwa U. Ibe ◽  
Shaeri Mukherjee
Keyword(s):  
Legionella Pneumophila ◽  
Nuclear Translocation ◽  
Bacterial Pathogen ◽  
Effector Proteins ◽  
Regulatory Control ◽  
Unfolded Protein ◽  
Bacterial Proteins ◽  
Protein Response ◽  
Upr Pathway ◽  
Target Gene Transcription

AbstractThe intracellular bacterial pathogen Legionella pneumophila (L.p.) secretes ~330 effector proteins into the host cell to sculpt an Endoplasmic Reticulum (ER)-derived replicative niche. We previously reported five L.p. effectors that inhibit IRE1, a key sensor of the homeostatic unfolded protein response (UPR) pathway. In this study, we discovered a subset of L.p. toxins that selectively activate the UPR sensor ATF6, resulting in its cleavage, nuclear translocation and target gene transcription without affecting other UPR sensors such as PERK. In a deviation from the conventional model, this L.p. dependent activation of ATF6 does not require its transport to the Golgi or its cleavage by the S1P/S2P proteases. We believe that our findings highlight the unique regulatory control that L.p. exerts upon the three UPR sensors and expand the repertoire of bacterial proteins that selectively perturb host homeostatic pathways.

scholarly journals Effectors Targeting the Unfolded Protein Response during Intracellular Bacterial Infection

2021 ◽  
Vol 9 (4) ◽  
pp. 705
Author(s):  
Manal H. Alshareef ◽  
Elizabeth L. Hartland ◽  
Kathleen McCaffrey
Keyword(s):  
Bacterial Infection ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Host Defense ◽  
Effector Proteins ◽  
Dual Nature ◽  
Unfolded Protein ◽  
Bacterial Replication ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.

scholarly journals Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaomei Liu ◽  
Yanyan Guo ◽  
Jun Wang ◽  
Liangliang Zhu ◽  
Linlin Gao
Keyword(s):  
Protein Kinase ◽  
Unfolded Protein Response ◽  
Binding Protein ◽  
Protein Kinase R ◽  
Pregnant Rats ◽  
Fetal Pancreas ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition in utero on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2α were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.

scholarly journals Biogenesis of the Spacious Coxiella-Containing Vacuole Depends on Host Transcription Factors TFEB and TFE3

2019 ◽  
Vol 88 (3) ◽  
Author(s):  
Bhavna Padmanabhan ◽  
Laura F. Fielden ◽  
Abderrahman Hachani ◽  
Patrice Newton ◽  
David R. Thomas ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Host Cell ◽  
Isotope Labeling ◽  
Nuclear Translocation ◽  
Bacterial Pathogen ◽  
Effector Proteins ◽  
Content Type ◽  
Cellular Processes ◽  
Type Iv ◽  
Lysosome Biogenesis

ABSTRACT Coxiella burnetii is an obligate intracellular bacterial pathogen that replicates inside the lysosome-derived Coxiella-containing vacuole (CCV). To establish this unique niche, C. burnetii requires the Dot/Icm type IV secretion system (T4SS) to translocate a cohort of effector proteins into the host cell, which modulate multiple cellular processes. To characterize the host-pathogen interactions that occur during C. burnetii infection, stable-isotope labeling by amino acids in cell culture (SILAC)-based proteomics was used to identify changes in the host proteome during infection of a human-derived macrophage cell line. These data revealed that the abundances of many proteins involved in host cell autophagy and lysosome biogenesis were increased in infected cells. Thus, the role of the host transcription factors TFEB and TFE3, which regulate the expression of a network of genes involved in autophagy and lysosomal biogenesis, were examined in the context of C. burnetii infection. During infection with C. burnetii, both TFEB and TFE3 were activated, as demonstrated by the transport of these proteins from the cytoplasm into the nucleus. The nuclear translocation of these transcription factors was shown to be dependent on the T4SS, as a Dot/Icm mutant showed reduced nuclear translocation of TFEB and TFE3. This was supported by the observation that blocking bacterial translation with chloramphenicol resulted in the movement of TFEB and TFE3 back into the cytoplasm. Silencing of the TFEB and TFE3 genes, alone or in combination, significantly reduced the size of the CCV, which indicates that these host transcription factors facilitate the expansion and maintenance of the organelle that supports C. burnetii intracellular replication.

scholarly journals Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2167 ◽  
Author(s):  
Lavinia Raimondi ◽  
Angela De Luca ◽  
Simona Fontana ◽  
Nicola Amodio ◽  
Viviana Costa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Extracellular Vesicle ◽  
Scientific Data ◽  
Daily Experience ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Protein Response ◽  
Upr Pathway

Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1α/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1α by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1α (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption.

scholarly journals A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response

2007 ◽  
Vol 177 (6) ◽  
pp. 1017-1027 ◽  
Author(s):  
Alicia A. Bicknell ◽  
Anna Babour ◽  
Christine M. Federovitch ◽  
Maho Niwa
Keyword(s):  
Cell Cycle ◽  
Unfolded Protein Response ◽  
Normal Cell ◽  
Growth Conditions ◽  
Unfolded Protein ◽  
Functional Capabilities ◽  
Cellular Events ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

The unfolded protein response (UPR) pathway helps cells cope with endoplasmic reticulum (ER) stress by activating genes that increase the ER's functional capabilities. We have identified a novel role for the UPR pathway in facilitating budding yeast cytokinesis. Although other cell cycle events are unaffected by conditions that disrupt ER function, cytokinesis is sensitive to these conditions. Moreover, efficient cytokinesis requires the UPR pathway even during unstressed growth conditions. UPR-deficient cells are defective in cytokinesis, and cytokinesis mutants activate the UPR. The UPR likely achieves its role in cytokinesis by sensing small changes in ER load and making according changes in ER capacity. We propose that cytokinesis is one of many cellular events that require a subtle increase in ER function and that the UPR pathway has a previously uncharacterized housekeeping role in maintaining ER plasticity during normal cell growth.

scholarly journals Protein Serine/Threonine Phosphatase Ptc2p Negatively Regulates the Unfolded-Protein Response by Dephosphorylating Ire1p Kinase

1998 ◽  
Vol 18 (4) ◽  
pp. 1967-1977 ◽  
Author(s):  
Ajith A. Welihinda ◽  
Witoon Tirasophon ◽  
Sarah R. Green ◽  
Randal J. Kaufman
Keyword(s):  
Unfolded Protein Response ◽  
Transmembrane Protein ◽  
Null Alleles ◽  
Dependent Manner ◽  
Unfolded Proteins ◽  
Interaction Domain ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

ABSTRACT Cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by increasing the transcription of the genes encoding ER-resident chaperone proteins. Ire1p is a transmembrane protein kinase that transmits the signal from unfolded proteins in the lumen of the ER by a mechanism that requires oligomerization andtrans-autophosphorylation of its cytoplasmic-nucleoplasmic kinase domain. Activation of Ire1p induces a novel spliced form ofHAC1 mRNA that produces Hac1p, a transcription factor that is required for activation of the transcription of genes under the control of the unfolded-protein response (UPR) element. Searching for proteins that interact with Ire1p in Saccharomyces cerevisiae, we isolated PTC2, which encodes a serine/threonine phosphatase of type 2C. The Ptc2p interaction with Ire1p is specific, direct, dependent on Ire1p phosphorylation, and mediated through a kinase interaction domain within Ptc2p. Ptc2p dephosphorylates Ire1p efficiently in an Mg2+-dependent manner in vitro. PTC2 is nonessential for growth and negatively regulates the UPR pathway. Strains carrying null alleles ofPTC2 have a three- to fourfold-increased UPR and increased levels of spliced HAC1 mRNA. Overexpression of wild-type Ptc2p but not catalytically inactive Ptc2p reduces levels of splicedHAC1 mRNA and attenuates the UPR, demonstrating that the phosphatase activity of Ptc2p is required for regulation of the UPR. These results demonstrate that Ptc2p downregulates the UPR by dephosphorylating Ire1p and reveal a novel mechanism of regulation in the UPR pathway upstream of the HAC1 mRNA splicing event.

Andrographolide Mitigates Unfolded Protein Response Pathway andApoptosis Involved in Chikungunya virus Infection

2020 ◽  
Vol 23 ◽  
Author(s):  
Swati Gupta ◽  
KP Mishra ◽  
Bhuvnesh Kumar ◽  
SB Singh ◽  
Lilly Ganju
Keyword(s):  
Protein Expression ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Chikungunya Virus ◽  
Rna Virus ◽  
Apoptosis Pathway ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
Protein Response ◽  
Upr Pathway

Background: Chikungunya virus (CHIKV) is an arthropod-borne RNA virus which induces host endoplasmic reticulum (ER) stress by accumulating unfolded or misfolded proteins. ER stress activates the unfolded protein response (UPR) pathway to enable proper protein folding and maintain cellular homeostasis. There is no approved drug or vaccine available for CHIKV treatment, therefore, a pharmacological countermeasure is warranted for preventing CHIKV infection. Objective: With a view to find a treatment modality for chikungunya infection, “andrographolide”; a plant-derived diterpenoid with reported antiviral, anti-inflammatory and immunomodulatory effects, was used to investigate its role in chikungunya induced unfolded protein stress and apoptosis. Methods: Cells and supernatant collected on andrographolide and VER-155008; a GRP78 inhibitor, treatment in CHIKV infected and mock-infected THP-1 cells were tested for differential expression of UPR pathway proteins including GRP78, PERK, EIF-2α, IRE-1α, XBP-1 and ATF6. Further, the inflammasome and apoptosis pathway proteins i.e. caspase-1, caspase-3 and PARP were tested by immunoblotting and cytokines i.e. IL-1β, IL-6 and IFN-γ were tested by ELISA. Results: Andrographolide treatment in CHIKV infected THP-1 cells significantly reduced IRE1α and downstream spliced XBP1 protein expression. Further, CHIKV induced apoptosis and viral protein expression was also reduced on andrographolide treatment. A comparative analysis of andrographolide verses VER-155008, confirmed that andrographolide surpasses the effects of VER-155008 in suppressing the CHIKV induced ER stress. Conclusion: The study, therefore, confirms that andrographolide is a potential remedy for chikungunya infection and suppresses CHIKV induced ER stress and apoptosis.

A Novel Unfolded Protein Response (UPR) Related 6 Genes Signature for Prognosis of Human Gastric Cancer

2020 ◽  
Author(s):  
XuYang Jia ◽  
RunZhi Huang ◽  
ShuYuan Xian ◽  
Yu Song ◽  
Hao Pan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Analysis ◽  
Clinical Practice ◽  
Cox Regression ◽  
Risk Group ◽  
Prognostic Signature ◽  
Prognostic Effect ◽  
Unfolded Protein ◽  
Protein Response ◽  
Upr Pathway

Abstract Background: Unfolded protein response (UPR) pathway has attracted increasing attention in the last few years for its close relation to cancer process like proliferation and drug resistance. However, few studies reported its prognostic effect in gastric cancer (GC). The purpose of this study is to identify the UPR expression in gastric cancer and construct a prognostic gene signature for clinical practice. Method: TCGA-STAD (gastric cancer cohort) was set as the training group and GSE84437 for validation. GSVA and GSEA was performed to identify the high expressed pathway in patients with gastric tumor. Following that, cox proportional hazard regression was adopted to screen genes correlated with survival in UPR path. Then, risk score for each patients was computed (FKBP14 value * (0.267719774) + TUBB2A value * (0.193233442) + SLC1A4 value * (-0.246893982) + SEC11A value * (0.484354542) + IFIT1 value * (0.152379968) + IGFBP1 value * (0.127045661)) and survival analysis was conducted between patients in high and low risk group according to their median risk score. A nomogram was built accordingly to guide clinical practice.Result: The UPR path was identified as the most highly expressed hallmark in GC with β of 32.98. A 6 genes prognostic signature was constructed according to the Cox regression and survival analysis obtained significant result where patients in low risk group showed longer OS (overall survival). The signature demonstrated an independent prognostic effect cox regression with a HR of 1.8. The external GSE84437 data proved the nomogram performed well in predicting 5 years OS. Conclusion: Our study identified that UPR pathway was highly activated in GC and a UPR related 6 genes prognostic signature demonstrated good performance. The 6 UPR related genes may serve as reliable prognostic biomarkers and potential therapeutic targets for GC treatment.

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