BLIMP-1 Is a Target of Cellular Stress and Downstream of the Unfolded Protein Response.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2207-2207
Author(s):  
Gina Doody ◽  
Sophie Stephenson ◽  
Reuben Tooze
Keyword(s):  
Cell Differentiation ◽  
Stress Response ◽  
Virus Infection ◽  
B Cell ◽  
Signaling Pathways ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Eif2α Kinase ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Human B lymphocyte-induced maturation protein-1 (BLIMP-1) was originally described as a repressor of the interferon-beta response to viral infection. Subsequently, the murine orthologue was identified as a regulator of plasma cell differentiation. The involvement of BLIMP-1 in hemopoietic differentiation is not restricted to the B-cell lineage as BLIMP-1 is induced during differentiation of myeloid progenitors. During in vitro macrophage and plasma cell differentiation the expression of BLIMP-1 is cytokine driven. However, the BLIMP-1 response to virus infection can be reproduced by transfection with double-stranded RNA (dsRNA), indicating that BLIMP-1 is a target of dsRNA responsive signaling pathways. A central regulator of the intracellular response to viral infection is the interferon-inducible double-stranded RNA activated kinase, PKR. PKR belongs to a family of kinases that phosphorylate the eukaryotic translation initiation factor 2-alpha (eIF2α) and activate common downstream signaling pathways. PERK, the endoplasmic reticulum (ER) PKR-homologue is activated during the unfolded protein response (UPR), a stress response involved in both macrophage activation and terminal B-cell differentiation. This suggested the hypothesis that BLIMP-1 may represent a shared target of signaling pathways in the response to cellular stresses such as virus infection and the UPR. In this study we demonstrate that BLIMP-1 is rapidly upregulated during the UPR in human myeloid and B-cell lines. This response is conserved in primary murine macrophages, in which mimics of physiological stress and classical activation stimuli also induce Blimp-1. During the UPR, BLIMP-1 mRNA is induced at the level of transcription, with enhanced recruitment of RNA polymerase II to the BLIMP-1 promoter. Furthermore the stress response is limited to induction of BLIMP-1α mRNA and does not affect levels of an alternate transcript encoding a truncated protein, BLIMP-1β. The common induction of BLIMP-1 mRNA by stimuli which trigger the UPR supports the hypothesis that BLIMP-1 is a target of the eIF2α kinase family. To test this hypothesis directly, we employed a dominant negative mutant PERK. Our data demonstrate that the BLIMP-1 response to UPR stress is dependent on an intact PERK signaling pathway. Collectively our results provide evidence for a novel link between cellular stress, the eIF2α kinase family and a regulator of differentiation in macrophages and B-cells.

scholarly journals Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1897 ◽  
Author(s):  
Alexander McQuiston ◽  
J Alan Diehl
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Transmembrane Protein ◽  
Downstream Signaling ◽  
Unfolded Protein ◽  
Evolutionarily Conserved ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is an evolutionarily conserved stress response to intra- and extracellular conditions that disrupt endoplasmic reticulum (ER) protein-folding capacity. The UPR is engaged by a variety of disease conditions, including most cancers as well as both metabolic and neurodegenerative disorders. Three transmembrane transducers—PERK, IRE1, and ATF6—are responsible for activating downstream signaling pathways that mediate the UPR and subsequent stress response pathways. PERK, an ER resident transmembrane protein kinase, initiates both pro-apoptotic and pro-survival signaling pathways. In the context of neoplasia, PERK and its downstream targets alter gene expression that can be both pro- and anti-tumorigenic. In this review, we discuss recent advances in understanding how canonical and non-canonical PERK-mediated signaling pathways influence cell fate, tumor progression, and tumor suppression and avenues for therapeutic intervention.

scholarly journals The unfolded protein response induced by Tembusu virus infection

2019 ◽  
Vol 15 (1) ◽  
Author(s):  
Dongmin Zhao ◽  
Jing Yang ◽  
Kaikai Han ◽  
Qingtao Liu ◽  
Huili Wang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Tembusu Virus ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Genotype 2 Strains of Porcine Reproductive and Respiratory Syndrome Virus Dysregulate Alveolar Macrophage Cytokine Production via the Unfolded Protein Response

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Wei-Yu Chen ◽  
William M. Schniztlein ◽  
Gabriela Calzada-Nova ◽  
Federico A. Zuckermann
Keyword(s):  
Virus Infection ◽  
Unfolded Protein Response ◽  
Cytokine Production ◽  
Translation Initiation Factor ◽  
Respiratory Syndrome Virus ◽  
Stress Sensor ◽  
Unfolded Protein ◽  
Tnf Α ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) infects alveolar macrophages (AMϕ), causing dysregulated alpha interferon (IFN-α) and tumor necrosis factor alpha (TNF-α) production through a mechanism(s) yet to be resolved. Here, we show that AMϕ infected with PRRSV secreted a reduced quantity of IFN-α following exposure of the cell to synthetic double-stranded RNA (dsRNA). This reduction did not correlate with reduced IFNA1 gene transcription. Rather, it coincided with two events that occurred late during infection and that were indicative of translational attenuation, specifically, the activation of eukaryotic translation initiation factor 2α (eIF2α) and the appearance of stress granules. Notably, the typical rapid production of TNF-α by AMϕ exposed to lipopolysaccharide (LPS) was suppressed or enhanced by PRRSV, depending on when the LPS exposure occurred after virus infection. If exposure was delayed until 6 h postinfection (hpi) so that the development of the cytokine response coincided with the time in which phosphorylation of eIF2α by the stress sensor PERK (protein kinase RNA [PKR]-like ER kinase) occurred, inhibition of TNF-α production was observed. However, if LPS exposure occurred at 2 hpi, prior to a detectable onset of eIF2α phosphorylation, a synergistic response was observed due to the earlier NF-κB activation via the stress sensor IRE1α (inositol-requiring kinase 1α). These results suggest that the asynchronous actions of two branches of the unfolded protein response (UPR), namely, IRE1α, and PERK, activated by ER stress resulting from the virus infection, are associated with enhancement or suppression of TNF-α production, respectively. IMPORTANCE The activation of AMϕ is controlled by the microenvironment to deter excessive proinflammatory cytokine responses to microbes that could impair lung function. However, viral pneumonias frequently become complicated by secondary bacterial infections, triggering severe inflammation, lung dysfunction, and death. Although dysregulated cytokine production is considered an integral component of the exacerbated inflammatory response in viral-bacterial coinfections, the mechanism responsible for this event is unknown. Here, we show that PRRSV replication in porcine AMϕ triggers activation of the IRE1α branch of the UPR, which causes a synergistic TNF-α response to LPS exposure. Thus, the severe pneumonias typically observed in pigs afflicted with PRRSV-bacterial coinfections could result from dysregulated, overly robust TNF-α production in response to opportunistic pathogens that is not commensurate with the typical restrained reaction by uninfected AMϕ. This notion could help in the design of therapies to mitigate the severity of viral and bacterial coinfections.

scholarly journals USP19 deubiquitinating enzyme inhibits muscle cell differentiation by suppressing unfolded-protein response signaling

2015 ◽  
Vol 26 (5) ◽  
pp. 913-923 ◽  
Author(s):  
Benjamin Wiles ◽  
Miao Miao ◽  
Erin Coyne ◽  
Louise Larose ◽  
Andrey V. Cybulsky ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Unfolded Protein Response ◽  
Muscle Cell ◽  
Deubiquitinating Enzyme ◽  
Muscle Cell Differentiation ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

USP19 deubiquitinating enzyme has two isoforms, cytoplasmic and endoplasmic reticulum (ER) localized. The ER-localized isoform specifically suppresses muscle cell differentiation in vitro and appears to do so by inhibiting the unfolded-protein response that occurs during such differentiation. In vivo, loss of USP19 promotes muscle regeneration following injury.

scholarly journals HY5, a positive regulator of light signaling, negatively controls the unfolded protein response inArabidopsis

2017 ◽  
Vol 114 (8) ◽  
pp. 2084-2089 ◽  
Author(s):  
Ganesh M. Nawkar ◽  
Chang Ho Kang ◽  
Punyakishore Maibam ◽  
Joung Hun Park ◽  
Young Jun Jung ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanism ◽  
26S Proteasome ◽  
Light Signaling ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

Light influences essentially all aspects of plant growth and development. Integration of light signaling with different stress response results in improvement of plant survival rates in ever changing environmental conditions. Diverse environmental stresses affect the protein-folding capacity of the endoplasmic reticulum (ER), thus evoking ER stress in plants. Consequently, the unfolded protein response (UPR), in which a set of molecular chaperones is expressed, is initiated in the ER to alleviate this stress. Although its underlying molecular mechanism remains unknown, light is believed to be required for the ER stress response. In this study, we demonstrate that increasing light intensity elevates the ER stress sensitivity of plants. Moreover, mutation of the ELONGATED HYPOCOTYL 5 (HY5), a key component of light signaling, leads to tolerance to ER stress. This enhanced tolerance ofhy5plants can be attributed to higher expression of UPR genes. HY5 negatively regulates the UPR by competing with basic leucine zipper 28 (bZIP28) to bind to the G-box–like element present in the ER stress response element (ERSE). Furthermore, we found that HY5 undergoes 26S proteasome-mediated degradation under ER stress conditions. Conclusively, we propose a molecular mechanism of crosstalk between the UPR and light signaling, mediated by HY5, which positively mediates light signaling, but negatively regulates UPR gene expression.

Cellular stress response and apoptosis in cancer therapy

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2603-2614 ◽  
Author(s):  
Ingrid Herr ◽  
Klaus-Michael Debatin
Keyword(s):  
Stress Response ◽  
Proteolytic Enzymes ◽  
Cellular Stress ◽  
Nuclear Factor Κb ◽  
Cellular Stress Response ◽  
Unfolded Protein ◽  
Anticancer Treatment ◽  
Mediate Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Anticancer treatment using cytotoxic drugs is considered to mediate cell death by activating key elements of the apoptosis program and the cellular stress response. While proteolytic enzymes (caspases) serve as main effectors of apoptosis, the mechanisms involved in activation of the caspase system are less clear. Two distinct pathways upstream of the caspase cascade have been identified. Death receptors, eg, CD95 (APO-1/Fas), trigger caspase-8, and mitochondria release apoptogenic factors (cytochrome c, Apaf-1, AIF), leading to the activation of caspase-9. The stressed endoplasmic reticulum (ER) contributes to apoptosis by the unfolded protein response pathway, which induces ER chaperones, and by the ER overload response pathway, which produces cytokines via nuclear factor-κB. Multiple other stress-inducible molecules, such as p53, JNK, AP-1, NF-κB, PKC/MAPK/ERK, and members of the sphingomyelin pathway have a profound influence on apoptosis. Understanding the complex interaction between different cellular programs provides insights into sensitivity or resistance of tumor cells and identifies molecular targets for rational therapeutic intervention strategies.

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