Abstract 292: The Role of the ATF6 Branch of the ER Stress Response in the Endocrine Heart

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Erik A Blackwood ◽  
Christopher C Glembotski
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Knockout Mice ◽  
Ex Vivo ◽  
Proteolytic Cleavage ◽  
Isolated Perfused Heart ◽  
Wild Type ◽  
Atrial Myocytes ◽  
Perfused Heart ◽  
Er Stress Response

Rationale: Atrial natriuretic peptide (ANP) is stored in the heart in large dense core granules of atrial myocytes as a biologically inactive precursor, pro-ANP. Hemodynamic stress and atrial stretch stimulate coordinate secretion and proteolytic cleavage of pro-ANP to its bioactive form, ANP, which promotes renal salt excretion and vasodilation, which, together contribute to decreasing blood pressure. While the ATF6 branch of the ER stress response has been studied in ventricular tissue mouse models of myocardial ischemia and pathological hypertrophy, roles for ATF6 and ER stress on the endocrine function of atrial myocytes have not been studied. Objective/Methods: To address this gap in our knowledge, we knocked down ATF6 in primary cultured neonatal rat atrial myocytes (NRAMs) using a chemical inhibitor of the proteolytic cleavage site enabling ATF6 activation and siRNA and measured ANP expression and secretion basally and in response to alpha- adrenergic agonist stimulation using phenylephrine. We also compared the ANP secretion from wild- type mice and ATF6 knockout mice in an ex vivo Langendorff model of the isolated perfused heart. Results: ATF6 knockdown in NRAMs significantly impaired basal and phenylephrine-stimulated ANP secretion. ATF6 knockout mice displayed lower levels of ANP in atrial tissue at baseline as well as after phenylephrine treatment. Similarly, in the ex vivo isolated perfused heart model, less ANP was detected in effluent of ATF6 knockout hearts compared to wild-type hearts. Conclusions: The ATF6 branch of the ER stress response is necessary for efficient co-secretional processing of pro-ANP to ANP and for agonist-stimulated ANP secretion from atrial myocytes. As ANP is secreted in a regulated manner in response to a stimulus and pro-ANP is synthesized and packaged through the classical secretory pathway, we posit that ATF6 is required for adequate expression, folding, trafficking, processing and secretion of biologically active ANP from the endocrine heart.

scholarly journals Constitutive Photomorphogenic 1 Enhances ER Stress Tolerance in Arabidopsis

2021 ◽  
Vol 22 (19) ◽  
pp. 10772
Author(s):  
Chang Ho Kang ◽  
Eun Seon Lee ◽  
Ganesh M. Nawkar ◽  
Joung Hun Park ◽  
Seong Dong Wi ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Stress Conditions ◽  
Negative Regulator ◽  
Light Signaling ◽  
Dependent Manner ◽  
Wild Type ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Mutant Locus

Interaction between light signaling and stress response has been recently reported in plants. Here, we investigated the role of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), a key regulator of light signaling, in endoplasmic reticulum (ER) stress response in Arabidopsis. The cop1-4 mutant Arabidopsis plants were highly sensitive to ER stress induced by treatment with tunicarmycin (Tm). Interestingly, the abundance of nuclear-localized COP1 increased under ER stress conditions. Complementation of cop1-4 mutant plants with the wild-type or variant types of COP1 revealed that the nuclear localization and dimerization of COP1 are essential for its function in plant ER stress response. Moreover, the protein amount of ELONGATED HYPOCOTYL 5 (HY5), which inhibits bZIP28 to activate the unfolded protein response (UPR), decreased under ER stress conditions in a COP1-dependent manner. Accordingly, the binding of bZIP28 to the BIP3 promoter was reduced in cop1-4 plants and increased in hy5 plants compared with the wild type. Furthermore, introduction of the hy5 mutant locus into the cop1-4 mutant background rescued its ER stress-sensitive phenotype. Altogether, our results suggest that COP1, a negative regulator of light signaling, positively controls ER stress response by partially degrading HY5 in the nucleus.

Endoplasmic reticulum accumulation of Kir6.2 without activation of ER stress response in islet cells from adult Sur1 knockout mice

2010 ◽  
Vol 340 (2) ◽  
pp. 335-346 ◽  
Author(s):  
Ihsane Marhfour ◽  
Jean-Christophe Jonas ◽  
Joëlle Marchandise ◽  
Alberte Lefevre ◽  
Jacques Rahier ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Knockout Mice ◽  
Islet Cells ◽  
Er Stress Response ◽  
Sur1 Knockout Mice

scholarly journals Hepatitis B Virus preS/S Truncation Mutant rtM204I/sW196* Increases Carcinogenesis through Deregulated HIF1A, MGST2, and TGFbi

2020 ◽  
Vol 21 (17) ◽  
pp. 6366
Author(s):  
Ming-Wei Lai ◽  
Kung-Hao Liang ◽  
Chau-Ting Yeh
Keyword(s):  
Hepatitis B Virus ◽  
Stress Response ◽  
Hepatitis B ◽  
Er Stress ◽  
Cdna Microarray ◽  
Cell Transformation ◽  
Wild Type ◽  
Gene Expressions ◽  
Er Stress Response ◽  
B Virus

Inevitable long-term therapy with nucleos(t)ide analogs in patients with chronic hepatitis B virus (HBV) infection has selected reverse-transcriptase (rt) mutants in a substantial proportion of patients. Some of these mutants introduce premature stop codons in the overlapping surface (s) gene, including rtA181T/sW172*, which has been shown to enhance oncogenicity. The oncogenicity of another drug-resistant mutant, rtM204I/sW196*, has not been studied. We constructed plasmids harboring rtM204I/sW196* and assessed the in vitro cell transformation, endoplasmic reticulum (ER) stress response, and xenograft tumorigenesis of the transformants. Cellular gene expression was analyzed by cDNA microarray and was validated. The rtM204I/sW196* transformants, compared with the control or wild type, showed enhanced transactivation activities for c-fos, increased cell proliferation, decreased apoptosis, more anchorage-independent growth, and enhanced tumor growth in mouse xenografts. X box-binding protein-1 (XBP1) splicing analysis showed no ER stress response. Altered gene expressions, including up-regulated MGST2 and HIF1A, and downregulated transforming growth factor beta-induced (TGFbi), were unveiled by cDNA microarray and validated by RT-qPCR. The TGFbi alteration occurred in transformants with wild type or mutated HBV. The altered MGST2 and HIF1A were found only with mutated HBV. The rtM204I/sW196* preS/S truncation may endorse the cell transformation and tumorigenesis ability via altered host gene expressions, including MGST2, HIF1A, and TGFbi. Downregulated TGFbi may be a common mechanism for oncogenicity in HBV surface truncation mutants.

scholarly journals Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy

2018 ◽  
Vol 38 (14) ◽  
Author(s):  
Matthew J. Brody ◽  
Davy Vanhoutte ◽  
Tobias G. Schips ◽  
Justin G. Boyer ◽  
Chinmay V. Bakshi ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Secretory Pathway ◽  
Tissue Injury ◽  
Wild Type ◽  
Content Type ◽  
Er Stress Response ◽  
Defective Mutant ◽  
Intracellular Vesicles ◽  
Thrombospondin 4

ABSTRACT Thrombospondins are stress-inducible secreted glycoproteins with critical functions in tissue injury and healing. Thrombospondin-4 (Thbs4) is protective in cardiac and skeletal muscle, where it activates an adaptive endoplasmic reticulum (ER) stress response, induces expansion of the ER, and enhances sarcolemmal stability. However, it is unclear if Thbs4 has these protective functions from within the cell, from the extracellular matrix, or from the secretion process itself. In this study, we generated transgenic mice with cardiac cell-specific overexpression of a secretion-defective mutant of Thbs4 to evaluate its exclusive intracellular and secretion-dependent functions. Like wild-type Thbs4, the secretion-defective mutant upregulates the adaptive ER stress response and expands the ER and intracellular vesicles in cardiomyocytes. However, only the secretion-defective Thbs4 mutant produces cardiomyopathy with sarcolemmal weakness and rupture that is associated with reduced adhesion-forming glycoproteins in the membrane. Similarly, deletion of Thbs4 in the mdx mouse model of Duchenne muscular dystrophy enhances cardiomyocyte membrane instability and cardiomyopathy. Finally, overexpression of the secretion-defective Thbs4 mutant in Drosophila , but not wild-type Thbs4, impaired muscle function and sarcomere alignment. These results suggest that transit through the secretory pathway is required for Thbs4 to augment sarcolemmal stability, while ER stress induction and vesicular expansion mediated by Thbs4 are exclusively intracellular processes.

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.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

Abstract 415: Cardioprotective Effects of Interleukin-15 in Immortalized Human Ventricular Cardiomyocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Marin Jane McBride ◽  
Kristina Durham ◽  
Bernardo L Trigatti
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Interleukin 2 ◽  
Cell Types ◽  
Human Cardiomyocytes ◽  
Er Stress Response ◽  
Distinct Cell ◽  
Receptor Chain ◽  
Interleukin 15 ◽  
Receptor Beta

Interleukin-15 (IL-15) is a pleotropic cytokine that has a profound effect on the proliferation, survival and differentiation of many distinct cell types. The IL-15 receptor complex has 3 subunits: the unique receptor chain IL-15 receptor alpha (IL-15Rα), and two receptor chains shared with interleukin-2 (IL-2) and/or other cytokines, referred to as IL-2 receptor beta (IL-2Rβ) and IL-2 receptor gamma/gamma common chain (IL-2Rγ/γc), respectively. To our knowledge, this is the first study to examine the effects of IL-15 in immortalized human cardiomyocytes. Data collected by RT-PCR shows mRNA expression of IL-15Rα, IL-2Rβ and IL-2 Rγ/γc in these cells. Additionally, western blotting for IL-15Rα, IL-2Rβ and IL-2 Rγ/γc confirms the presence of all three IL-15 receptors. Early experiments examining the effect of IL-15 on cardiomyocyte cell survival show a statistically significant protective effect of IL-15 on the survival of cells exposed to tunicamycin, a pharamacological endoplasmic reticulum (ER) stress inducing agent. These findings suggest that IL-15 signaling may be an important cardioprotective pathway that is involved in the cardiac ER stress response. As ER stress is a major component of multiple different cardiac pathologies, such as myocardial infarction, heart failure and diabetes, uncovering the molecular mechanism by which IL-15 protects the heart will allow for deeper understanding of the cardiac ER stress response.

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