scholarly journals The Unfolded Protein Response in the Protozoan Parasite Toxoplasma gondii Features Translational and Transcriptional Control

2013 ◽  
Vol 12 (7) ◽  
pp. 979-989 ◽  
Author(s):  
Bradley R. Joyce ◽  
Zoi Tampaki ◽  
Kami Kim ◽  
Ronald C. Wek ◽  
William J. Sullivan
Keyword(s):  
Gene Expression ◽  
Toxoplasma Gondii ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Process ◽  
Α Subunit ◽  
Content Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The unfolded protein response (UPR) is an important regulatory network that responds to perturbations in protein homeostasis in the endoplasmic reticulum (ER). In mammalian cells, the UPR features translational and transcriptional mechanisms of gene expression aimed at restoring proteostatic control. A central feature of the UPR is phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2) by PERK (EIF2AK3/PEK), which reduces the influx of nascent proteins into the ER by lowering global protein synthesis, coincident with preferential translation of key transcription activators of genes that function to expand the processing capacity of this secretory organelle. Upon ER stress, the apicomplexan parasite Toxoplasma gondii is known to induce phosphorylation of Toxoplasma eIF2α and lower translation initiation. To characterize the nature of the ensuing UPR in this parasite, we carried out microarray analyses to measure the changes in the transcriptome and in translational control during ER stress. We determined that a collection of transcripts linked with the secretory process are induced in response to ER stress, supporting the idea that a transcriptional induction phase of the UPR occurs in Toxoplasma. Furthermore, we determined that about 500 gene transcripts showed enhanced association with translating ribosomes during ER stress. Many of these target genes are suggested to be involved in gene expression, including JmjC5, which continues to be actively translated during ER stress. This study indicates that Toxoplasma triggers a UPR during ER stress that features both translational and transcriptional regulatory mechanisms, which is likely to be important for parasite invasion and development.

scholarly journals The PGRS Domain of Mycobacterium tuberculosis PE_PGRS Protein Rv0297 Is Involved in Endoplasmic Reticulum Stress-Mediated Apoptosis through Toll-Like Receptor 4

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Sonam Grover ◽  
Tarina Sharma ◽  
Yadvir Singh ◽  
Sakshi Kohli ◽  
Manjunath P. ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mycobacterium Tuberculosis ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The genome of Mycobacterium tuberculosis , the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca 2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism. IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.

The Unfolded Protein Response Is a Determinant of Disease Actvity in Waldenstrom’s Macroglobulinemia (WM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 996-996
Author(s):  
Xavier Leleu ◽  
Lian Xu ◽  
Daniel D. Santos ◽  
Allen W. Ho ◽  
Zachary R. Hunter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Waldenström’S Macroglobulinemia ◽  
Unfolded Protein ◽  
Waldenstrom's Macroglobulinemia ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Waldenström's Macroglobulinemia

Abstract The unfolded protein response (UPR) maintains the quality of newly synthesized secretory and transmembrane proteins such as immunoglobulins in the endoplasmic reticulum (ER) of eukaryotic cells. The most proximal sensors of the UPR are the ATF6, IRE1a-Xbp1, and PERK proteins. Bip, an ER stress-induced pro-survival molecular chaperone, controls the trafficking of Atf6 and is considered as an indicator of the onset of the UPR. EDEM, downstream of Xbp1 splicing, regulates the extraction of misfolded proteins into the cytosol for proteasome-mediated destruction. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected. We studied the UPR stress system in patients with Waldenstrom’s Macroglobulinemia (WM), a B-cell disorder characterized by excess secretion of IgM. As part of these efforts, we examined the UPR genes Bip-Atf6, Ire1a-Xbp1, Perk, as well as genes downstream of the UPR pathway including Xbp1 spliced-Edem, eIF2a and Gadd34 using semi-quantitative PCR analysis of CD19+ selected bone marrow lymphoplasmacytic cells (LPC) from 46 patients with the consensus panel diagnosis of WM. We found that UPR gene expression was highly heterogeneous with 16 (35%) patients expressing all genes, whilst 11 patients (24%) expressed only Xbp1 and Edem. Among patients expressing all UPR genes, median serum IgM (p=0.025) and B2M (p=0.05) levels, as well as bone marrow involvement (p=0.06) were higher, with levels of Bip showing greatest correlation to serum IgM and B2M levels, and BM involvement (p=0.01). These results confirm that UPR gene expression is related to disease activity in WM, and suggest a particular role for Bip as a prognostic factor in this disease.

scholarly journals Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

2016 ◽  
Vol 27 (9) ◽  
pp. 1536-1551 ◽  
Author(s):  
Michael E. Fusakio ◽  
Jeffrey A. Willy ◽  
Yongping Wang ◽  
Emily T. Mirek ◽  
Rana J. T. Al Baghdadi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cholesterol Metabolism ◽  
Unfolded Protein ◽  
Expression Of Genes ◽  
The Unfolded Protein Response ◽  
Protein Response

Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins—PERK (PEK/EIF2AK3), IRE1, and ATF6—is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera.

scholarly journals Puf4 Regulates both Splicing and Decay of HXL1 mRNA Encoding the Unfolded Protein Response Transcription Factor in Cryptococcus neoformans

2015 ◽  
Vol 14 (4) ◽  
pp. 385-395 ◽  
Author(s):  
Virginia E. Glazier ◽  
Jan Naseer Kaur ◽  
Nancy T. Brown ◽  
Ashley A. Rivera ◽  
John C. Panepinto
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cryptococcus Neoformans ◽  
Content Type ◽  
Unfolded Protein ◽  
Puf Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Unconventional Splicing

ABSTRACT The endoplasmic reticulum (ER) responds to errors in protein folding or processing by induction of the unfolded protein response (UPR). During conditions of ER stress, unconventional splicing of an mRNA encoding the UPR-responsive transcription factor occurs at the ER surface, resulting in activation of the UPR. UPR activation is necessary for adaptation to ER stress and for the pathogenic fungus Cryptococcus neoformans is an absolute requirement for temperature adaptation and virulence. In this study, we have determined that C. neoformans has co-opted a conserved PUF RNA binding protein to regulate the posttranscriptional processing of the HXL1 mRNA encoding the UPR transcription factor. PUF elements were identified in both the 5′ and 3′ untranslated regions of the HXL1 transcript, and both elements bound Puf4. Deletion of PUF4 resulted in delayed unconventional splicing of HXL1 mRNA and delayed induction of Hxl1 target genes. In addition, the HXL1 transcript was stabilized in the absence of Puf4. The puf4 Δ mutant exhibited temperature sensitivity but was as virulent as the wild type, despite a reduction in fungal burden in the brains of infected mice. Our results reveal a novel regulatory role in which a PUF protein influences the unconventional splicing of the mRNA encoding the UPR-responsive transcription factor. These data suggest a unique role for a PUF protein in controlling UPR kinetics via the posttranscriptional regulation of the mRNA encoding the UPR transcription factor Hxl1.

scholarly journals Attenuated Induction of the Unfolded Protein Response in Adult Human Primary Astrocytes in Response to Recurrent Low Glucose

2021 ◽  
Vol 12 ◽  
Author(s):  
Paul G. Weightman Potter ◽  
Sam J. Washer ◽  
Aaron R. Jeffries ◽  
Janet E. Holley ◽  
Nick J. Gutowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Human Astrocytes ◽  
Low Glucose ◽  
Primary Astrocytes ◽  
The Unfolded Protein Response ◽  
Protein Response

Aims/hypothesisRecurrent hypoglycaemia (RH) is a major side-effect of intensive insulin therapy for people with diabetes. Changes in hypoglycaemia sensing by the brain contribute to the development of impaired counterregulatory responses to and awareness of hypoglycaemia. Little is known about the intrinsic changes in human astrocytes in response to acute and recurrent low glucose (RLG) exposure.MethodsHuman primary astrocytes (HPA) were exposed to zero, one, three or four bouts of low glucose (0.1 mmol/l) for three hours per day for four days to mimic RH. On the fourth day, DNA and RNA were collected. Differential gene expression and ontology analyses were performed using DESeq2 and GOseq, respectively. DNA methylation was assessed using the Infinium MethylationEPIC BeadChip platform.Results24 differentially expressed genes (DEGs) were detected (after correction for multiple comparisons). One bout of low glucose exposure had the largest effect on gene expression. Pathway analyses revealed that endoplasmic-reticulum (ER) stress-related genes such as HSPA5, XBP1, and MANF, involved in the unfolded protein response (UPR), were all significantly increased following low glucose (LG) exposure, which was diminished following RLG. There was little correlation between differentially methylated positions and changes in gene expression yet the number of bouts of LG exposure produced distinct methylation signatures.Conclusions/interpretationThese data suggest that exposure of human astrocytes to transient LG triggers activation of genes involved in the UPR linked to endoplasmic reticulum (ER) stress. Following RLG, the activation of UPR related genes was diminished, suggesting attenuated ER stress. This may be a consequence of a successful metabolic adaptation, as previously reported, that better preserves intracellular energy levels and a reduced necessity for the UPR.

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 Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

Sign in / Sign up

Export Citation Format

Share Document