Abstract 281: Sigma-1 Receptor Dependent Pathway for a Protective Endoplasmic Reticulum Stress Response in Cardiomyocytes

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Shafiul Alam ◽  
A. Wayne Orr ◽  
Christopher B. Pattillo ◽  
Md. Shenuarin Bhuiyan
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Nuclear Transport ◽  
Neuronal Cell ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Sigma 1 Receptor ◽  
Er Stress Response ◽  
Chop Expression ◽  
Sigma 1

Rationale: We recently reported that Sigma 1 receptor (Sigmar1) is a molecular chaperone protein highly expressed in the heart. Studies involving different cancer and neuronal cell lines indicated Sigmar1 resides in the mitochondrion-associated ER membrane (MAM). However, the subcellular localization of Sigmar1 and the molecular function in ER-stress remains unknown in cardiomyocytes. Here we describe a function for Sigmar1 as an effector of an adaptive ER stress response. Objective: The objective of this study was to elucidate functional roles of Simgar1 in ER-stress in cardiomyocytes. Methods and Results: Subcellular fractionation of the mouse heart showed extensive localization of Sigmar1 in the MAM and mitochondrial fraction. To define the function in an ER-stress response, we used small interfering RNA-mediated Sigmar1 knockdown and adenovirus-mediated overexpression in cultured neonatal rat ventricular cardiomyocytes. We treated with tunicamycin to induce ER stress. In cardiomyocytes, tunicamycin increased C/EBP-homologous protein (CHOP) expression; Sigmar1 overexpression significantly decreased the CHOP expression. We found that Sigmar1 overexpression was sufficient to activate the nuclear transport of spliced X-box binding protein 1 (Xbp1s) with minimal effects in other adaptive ER stress proteins. Sigmar1 knockdown decreased the nuclear transport of Xbp1s, increased the expression of nuclear CHOP and significantly increased LDH release. We also observed significant Sigmar1 expression dependent increases in mitochondrial respiration in cardiomyocytes under ER stress. Hence, Sigmar1 can function inside the cell during disease remodeling to augment ER function and protect through a mechanism involving regulation of Xbp1s. Conclusions: Sigmar1 is an essential component of the adaptive ER stress response in cardiomyocytes. Sigmar1 can regulate ER-stress induced CHOP expression by activating XBP1s signaling in cardiomyocytes. Therefore, Sigmar1 residing at the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-response signaling between the ER and mitochondria.

scholarly journals Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Shafiul Alam ◽  
Chowdhury S. Abdullah ◽  
Richa Aishwarya ◽  
A. Wayne Orr ◽  
James Traylor ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Neonatal Rat ◽  
Cellular Toxicity ◽  
Sigma 1 Receptor ◽  
Homologous Protein ◽  
Er Stress Response ◽  
Chop Expression ◽  
Stress Pathway

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes.

scholarly journals Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ken-ichiro Tanaka ◽  
Misato Kasai ◽  
Mikako Shimoda ◽  
Ayane Shimizu ◽  
Maho Kubota ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Trace Metals ◽  
Er Stress ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Endoplasmic Reticulum Stress Response ◽  
Dependent Manner ◽  
Er Stress Response

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.

scholarly journals Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

2020 ◽  
Vol 11 ◽  
Author(s):  
José Miguel Vela
Keyword(s):  
Stress Response ◽  
Viral Replication ◽  
Er Stress ◽  
Host Cell ◽  
Drug Repurposing ◽  
Host Protein ◽  
Unique Challenge ◽  
Sigma 1 Receptor ◽  
Sigma 1

Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

Abstract 467: ATF6B and ATF6A Play Complimentary Roles in Mediating Adaptive and Maladaptive Signaling in Cardiac Myocytes

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Shivsmriti Koul ◽  
Jung-kang Jin ◽  
Clifford M Hogan ◽  
Christopher C Glembotski
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Stress Response ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemic Heart ◽  
Neonatal Rat ◽  
Loss Of Function ◽  
Er Stress Response ◽  
Stress Response Genes

Rationale: ATF6α and ATF6β are endoplasmic reticulum (ER) transmembrane proteins that sense the accumulation of toxic misfolded proteins in the ER of cardiomyocytes, which can be brought about by ER stresses as ischemia. Upon ER stress, ATF6α is proteolytically cleaved into a transcription factor that binds to ER stress response elements (ERSEs) and increases expression of cardioprotective genes that restore ER protein folding. If ER proteostasis is not restored, maladaptive signaling is initiated. ATF6β is also proteolytically cleaved during ER stress, binds to the same ERSEs as ATF6α, but does not induce transcription. Hence it is clear from the above studies done in cancer cells that there are some marked similarities and differences between ATF6α and ATF6β. However, the relative roles of ATF6α and ATF6β have not been studied in the heart, where they might work in concert to mediate the dynamic switch from adaptive to maladaptive gene programing during myocardial pathology. Methods: We used neonatal rat ventricular myocytes (NRVMs) to explore the effects of ATF6α or ATF6β loss-of-function in cells treated with the ER stressor, thapsigargin (TG), which mimics ischemic heart disease. Results: In NRVM treated with TG, knockdown of ATF6β resulted in much more pronounced cell death in isolated myocytes than knockdown of ATF6α. Consistent with this finding, transcriptome analyses showed that compared to knocking down ATF6α, knockdown of ATF6β upregulated much more maladaptive, cell death-inducing genes and downregulated more cardioprotective genes. Surprisingly, knockdown of either ATF6α or ATF6β downregulated some common adaptive ER stress response genes, such as GRP78 and Derlin while also upregulating common maladaptive ER stress response genes, such as CHOP, Bcl2, Bax. Conclusion: These data indicate that both ATF6α and ATF6 β are needed for optimal viability of NRVM subjected to ER stress. There is a common, as well as differential gene regulation program controlled by these two isoforms of ATF6. Importantly, this study demonstrates a novel mechanism by which these two isoforms of ATF6 interact to govern the progression from adaptive to maladaptive ER stress signaling during chronic misfolding of ER proteins that occurs in ischemic heart disease.

scholarly journals Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer's disease

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 180024 ◽  
Author(s):  
Shoko Hashimoto ◽  
Takaomi C. Saido
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Mouse Models ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Er Stress Response

The endoplasmic reticulum (ER) stress response is regarded as an important process in the aetiology of Alzheimer's disease (AD). The accumulation of pathogenic misfolded proteins and the disruption of intracellular calcium (Ca 2+ ) signalling are considered to be fundamental mechanisms that underlie the induction of ER stress, leading to neuronal cell death. Indeed, a number of studies have proposed molecular mechanisms linking ER stress to AD pathogenesis based on results from in vitro systems and AD mouse models. However, stress responsivity was largely different between each mouse model, even though all of these models display AD-related pathologies. While several reports have shown elevated ER stress responses in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) AD mouse models, we and other groups, in contrast, observed no such ER stress response in APP-single-Tg or App -knockin mice. Therefore, it is debatable whether the ER stress observed in APP and PS1 double-Tg mice is due to AD pathology. From these findings, the roles of ER stress in AD pathogenesis needs to be carefully addressed in future studies. In this review, we summarize research detailing the relationship between ER stress and AD, and analyse the results in detail.

Targeted regulation of lymphocytic ER stress response with an overall immunosuppression to alleviate allograft rejection

Biomaterials ◽  
2021 ◽  
pp. 120757
Author(s):  
Yingying Shi ◽  
Yichao Lu ◽  
Chunqi Zhu ◽  
Zhenyu Luo ◽  
Xiang Li ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Allograft Rejection ◽  
Er Stress Response

scholarly journals Highly Specialized Ubiquitin-Like Modifications: Shedding Light into the UFM1 Enigma

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 255
Author(s):  
Katharina F. Witting ◽  
Monique P.C. Mulder
Keyword(s):  
Dna Repair ◽  
Stress Response ◽  
Embryonic Development ◽  
Er Stress ◽  
Unmet Needs ◽  
Biological Function ◽  
Post Translational Modification ◽  
Er Stress Response ◽  
Cellular Events ◽  
Complex Signaling

Post-translational modification with Ubiquitin-like proteins represents a complex signaling language regulating virtually every cellular process. Among these post-translational modifiers is Ubiquitin-fold modifier (UFM1), which is covalently attached to its substrates through the orchestrated action of a dedicated enzymatic cascade. Originally identified to be involved embryonic development, its biological function remains enigmatic. Recent research reveals that UFM1 regulates a variety of cellular events ranging from DNA repair to autophagy and ER stress response implicating its involvement in a variety of diseases. Given the contribution of UFM1 to numerous pathologies, the enzymes of the UFM1 cascade represent attractive targets for pharmacological inhibition. Here we discuss the current understanding of this cryptic post-translational modification especially its contribution to disease as well as expand on the unmet needs of developing chemical and biochemical tools to dissect its role.

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