scholarly journals Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

2021 ◽  
Vol 22 (20) ◽  
pp. 11049
Author(s):  
Lucie Crouzier ◽  
Morgane Denus ◽  
Elodie M. Richard ◽  
Amarande Tavernier ◽  
Camille Diez ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Mitochondrial Activity ◽  
Sigma 1 Receptor ◽  
Unfolded Protein ◽  
Sigma 1 ◽  
Protein Response ◽  
The Impact

The sigma-1 receptor (S1R) is a highly conserved transmembrane protein highly enriched in mitochondria-associated endoplasmic reticulum (ER) membranes, where it interacts with several partners involved in ER-mitochondria Ca2+ transfer, activation of the ER stress pathways, and mitochondria function. We characterized a new S1R deficient zebrafish line and analyzed the impact of S1R deficiency on visual, auditory and locomotor functions. The s1r+25/+25 mutant line showed impairments in visual and locomotor functions compared to s1rWT. The locomotion of the s1r+25/+25 larvae, at 5 days post fertilization, was increased in the light and dark phases of the visual motor response. No deficit was observed in acoustic startle response. A critical role of S1R was shown in ER stress pathways and mitochondrial activity. Using qPCR to analyze the unfolded protein response genes, we observed that loss of S1R led to decreased levels of IRE1 and PERK-related effectors and increased over-expression of most of the effectors after a tunicamycin challenge. Finally, S1R deficiency led to alterations in mitochondria bioenergetics with decreased in basal, ATP-linked and non-mitochondrial respiration and following tunicamycin challenge. In conclusion, this new zebrafish model confirmed the importance of S1R activity on ER-mitochondria communication. It will be a useful tool to further analyze the physiopathological roles of S1R.

scholarly journals Loss of BOK Has a Minor Impact on Acetaminophen Overdose-Induced Liver Damage in Mice

2021 ◽  
Vol 22 (6) ◽  
pp. 3281
Author(s):  
Samara Naim ◽  
Yuniel Fernandez-Marrero ◽  
Simone de Brot ◽  
Daniel Bachmann ◽  
Thomas Kaufmann
Keyword(s):  
Liver Injury ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Western World ◽  
Liver Necrosis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
A Minor ◽  
Protein Response ◽  
The Impact

Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury. We therefore investigated the impact of the loss of BOK following APAP overdosing in mice. Surprisingly, we observed sex-dependent differences in the activation of the unfolded protein response (UPR) in both wildtype (WT) and Bok-/- mice, with increased activation of JNK in females compared with males. Loss of BOK led to a decrease in JNK activation and a reduced percentage of centrilobular necrosis in both sexes after APAP treatment; however, this protection was more pronounced in Bok-/- females. Nevertheless, serum ALT and AST levels of Bok-/- and WT mice were comparable, indicating that there was no major difference in the overall outcome of liver injury. We conclude that after APAP overdosing, loss of BOK affects initiating signaling steps linked to ER stress, but has a more minor impact on the outcome of liver necrosis. Furthermore, we observed sex-dependent differences that might be worthwhile to investigate.

scholarly journals The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

2021 ◽  
Vol 12 ◽  
Author(s):  
Mei Xue ◽  
Li Feng
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Drug Targets ◽  
Current Knowledge ◽  
Wide Spectrum ◽  
Unfolded Protein ◽  
Coronavirus Infection ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

Coronavirus is an important pathogen with a wide spectrum of infection and potential threats to humans and animals. Its replication occurs in the cytoplasm and is closely related to the endoplasmic reticulum (ER). Studies reported that coronavirus infection causes ER stress, and cells simultaneously initiate unfolded protein response (UPR) to alleviate the disturbance of ER homeostasis. Activation of the three branches of UPR (PERK, IRE1, and ATF6) modulates various signaling pathways, such as innate immune response, microRNA, autophagy, and apoptosis. Therefore, a comprehensive understanding of the relationship between coronavirus and ER stress is helpful to understand the replication and pathogenesis of coronavirus. This paper summarizes the current knowledge of the complex interplay between coronavirus and UPR branches, focuses on the effect of ER stress on coronavirus replication and coronavirus resistance to host innate immunity, and summarizes possible drug targets to regulate the impact of coronavirus infection.

scholarly journals ADP-ribose Transferase PARP16 Mediated-unfolded Protein Response Contributes to Neuronal Cell Damage in Cerebral Ischemia/Reperfusion

2021 ◽  
Author(s):  
Jinghuan Wang ◽  
zhenghua Su ◽  
wen Zhong ◽  
haibi Su ◽  
Jie Xu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cortical Neurons ◽  
Cell Damage ◽  
Transmembrane Protein ◽  
Ischemia Reperfusion ◽  
Neuronal Cell ◽  
Unfolded Protein ◽  
Protein Response

Abstract Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function and activating the unfolded protein response (UPR). PARP16 is the only an active ADP-ribosyl transferase known tail-anchored ER transmembrane protein with a cytosolic catalytic domain. Here, we find PARP16 is highly expressed in ischemic cerebral hemisphere and Oxygen-glucose deprivation (OGD)-treated immortalized hippocampal neuroblasts HT22 cells. Using adeno-associated virus-mediated knockdown PARP16 mice, we find knockdown PARP16 decreases infarct demarcations and has a better neurological outcome after ischemic stroke. Our data indicate PARP16 overexpression promotes ER stress-mediated cell damage in primary cortical neurons, in turn, knockdown PARP16 decreases ER stress and neuronal death caused by OGD. Furthermore, PARP16 functions mechanistically as ADP-ribosyltransferase to modulate the level of ribosylation of the corresponding PERK and IRE1α arm of the UPR, and that such modification is required for activation of PERK and IRE1α. Indeed, pharmacological stimulation of the UPR using Brefeldin A counteracts knockdown of PARP16-mediated neuronal protection in OGD. On other hand, when an ER inhibitor Tauroursodeoxycholic acid present, permit more obvious protection and inactivation of PERK and IRF1α caused by knockdown of PARP16. In conclusion, PARP16 plays a crucial role in post-ischemic UPR and the knockdown of PARP16 alleviates brain injury after ischemic stroke. The rationale of this study is to explore the potentials of the PARP16-PERK/IRE1α axis as a target for neuronal survival in ischemic stroke.

scholarly journals The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 333 ◽  
Author(s):  
Alberto M. Martelli ◽  
Francesca Paganelli ◽  
Francesca Chiarini ◽  
Camilla Evangelisti ◽  
James A. McCubrey
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Critical Role ◽  
Cell Protein ◽  
Acute Leukemias ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Novel Therapeutic

The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

scholarly journals ATF6 Activated by Proteolysis Binds in the Presence of NF-Y (CBF) Directly to the cis-Acting Element Responsible for the Mammalian Unfolded Protein Response

2000 ◽  
Vol 20 (18) ◽  
pp. 6755-6767 ◽  
Author(s):  
Hiderou Yoshida ◽  
Tetsuya Okada ◽  
Kyosuke Haze ◽  
Hideki Yanagi ◽  
Takashi Yura ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Intracellular Signaling ◽  
Transmembrane Protein ◽  
Consensus Sequence ◽  
Soluble Form ◽  
Dominant Negative Mutant ◽  
Unfolded Protein ◽  
Protein Response

ABSTRACT Transcription of genes encoding molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) is induced by accumulation of unfolded proteins in the ER. This intracellular signaling, known as the unfolded protein response (UPR), is mediated by thecis-acting ER stress response element (ERSE) in mammals. In addition to ER chaperones, the mammalian transcription factor CHOP (also called GADD153) is induced by ER stress. We report here that the transcription factor XBP-1 (also called TREB5) is also induced by ER stress and that induction of CHOP and XBP-1 is mediated by ERSE. The ERSE consensus sequence is CCAAT-N9-CCACG. As the general transcription factor NF-Y (also known as CBF) binds to CCAAT, CCACG is considered to provide specificity in the mammalian UPR. We recently found that the basic leucine zipper protein ATF6 isolated as a CCACG-binding protein is synthesized as a transmembrane protein in the ER, and ER stress-induced proteolysis produces a soluble form of ATF6 that translocates into the nucleus. We report here that overexpression of soluble ATF6 activates transcription of the CHOP and XBP-1 genes as well as of ER chaperone genes constitutively, whereas overexpression of a dominant negative mutant of ATF6 blocks the induction by ER stress. Furthermore, we demonstrated that soluble ATF6 binds directly to CCACG only when CCAAT exactly 9 bp upstream of CCACG is bound to NF-Y. Based on these and other findings, we concluded that specific and direct interactions between ATF6 and ERSE are critical for transcriptional induction not only of ER chaperones but also of CHOP and XBP-1.

scholarly journals The unfolded protein response in Pichia pastoris without external stressing stimuli

2020 ◽  
Vol 20 (7) ◽  
Author(s):  
Yasmin Nabilah Binti Mohd Fauzee ◽  
Naoki Taniguchi ◽  
Yuki Ishiwata-Kimata ◽  
Hiroshi Takagi ◽  
Yukio Kimata
Keyword(s):  
Pichia Pastoris ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Gene Knockout ◽  
Transmembrane Protein ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

ABSTRACT Dysfunction or capacity shortage of the endoplasmic reticulum (ER) is cumulatively called ER stress and provokes the unfolded protein response (UPR). In various yeast species, the ER-located transmembrane protein Ire1 is activated upon ER stress and performs the splicing reaction of HAC1 mRNA, the mature form of which is translated into a transcription factor protein that is responsible for the transcriptome change on the UPR. Here we carefully assessed the splicing of HAC1 mRNA in Pichia pastoris (Komagataella phaffii) cells. We found that, inconsistent with previous reports by others, the HAC1 mRNA was substantially, but partially, spliced even without ER-stressing stimuli. Unlike Saccharomyces cerevisiae, growth of P. pastoris was significantly retarded by the IRE1-gene knockout mutation. Moreover, P. pastoris cells seemed to push more abundant proteins into the secretory pathway than S. cerevisiae cells. We also suggest that P. pastoris Ire1 has the ability to control its activity stringently in an ER stress-dependent manner. We thus propose that P. pastoris cells are highly ER-stressed possibly because of the high load of endogenous proteins into the ER.

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.

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