scholarly journals Protein Disulfide Isomerase Superfamily in Disease and the Regulation of Apoptosis

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
C. Grek ◽  
D.M. Townsend
Keyword(s):  
Protein Folding ◽  
Er Stress ◽  
Cell Fate ◽  
Molecular Chaperones ◽  
Molecular Mechanisms ◽  
Disulfide Isomerases ◽  
Apoptotic Pathways ◽  
Er Homeostasis ◽  
Protein Disulfide

AbstractCellular homeostasis requires the balance of a multitude of signaling cascades that are contingent upon the essential proteins being properly synthesized, folded and delivered to appropriate subcellular locations. In eukaryotic cells the endoplasmic reticulum (ER) is a specialized organelle that is the central site of synthesis and folding of secretory, membrane and a number of organelletargeted proteins. The integrity of protein folding is enabled by the presence of ATP, Ca++, molecular chaperones, as well as an oxidizing redox environment. The imbalance between the load and capacity of protein folding results in a cellular condition known as ER stress. Failure of these pathways to restore ER homeostasis results in the activation of apoptotic pathways. Protein disulfide isomerases (PDI) compose a superfamily of oxidoreductases that have diverse sequences and are localized in the ER, nucleus, cytosol, mitochondria and cell membrane. The PDI superfamily has multiple functions including, acting as molecular chaperones, protein-binding partners, and hormone reservoirs. Recently , PDI family members have been implicated in the regulation of apoptotic signaling events. The complexities underlying the molecular mechanisms that define the switch from pro-survival to pro-death response are evidenced by recent studies that reveal the roles of specific chaperone proteins as integration points in signaling pathways that determine cell fate. The following review discusses the dual role of PDI in cell death and survival during ER stress.

scholarly journals Analysis of the Isomerase and Chaperone-Like Activities of an Amebic PDI (EhPDI)

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Rosa E. Mares ◽  
Alexis Z. Minchaca ◽  
Salvador Villagrana ◽  
Samuel G. Meléndez-López ◽  
Marco A. Ramos
Keyword(s):  
Protein Folding ◽  
Disulfide Bonds ◽  
Molecular Mechanisms ◽  
Thermal Inactivation ◽  
Initial Step ◽  
E Coli ◽  
Isomerase Activity ◽  
Disulfide Isomerases ◽  
Protein Disulfide

Protein disulfide isomerases (PDI) are eukaryotic oxidoreductases that catalyze the formation and rearrangement of disulfide bonds during folding of substrate proteins. Structurally, PDI enzymes share as a common feature the presence of at least one active thioredoxin-like domain. PDI enzymes are also involved in holding, refolding, and degradation of unfolded or misfolded proteins during stressful conditions. TheEhPDI enzyme (a 38 kDa polypeptide with two active thioredoxin-like domains) has been used as a model to gain insights into protein folding and disulfide bond formation inE. histolytica. Here, we performed a functional complementation assay, using a ΔdsbC mutant ofE. coli, to test whetherEhPDI exhibits isomerase activityin vivo. Our preliminary results showed thatEhPDI exhibits isomerase activity; however, further mutagenic analysis revealed significant differences in the functional role of each thioredoxin-like domain. Additional studies confirmed thatEhPDI protects heat-labile enzymes against thermal inactivation, extending our knowledge about its chaperone-like activity. The characterization ofEhPDI, as an oxidative folding catalyst with chaperone-like function, represents the initial step to dissect the molecular mechanisms involved in protein folding inE. histolytica.

scholarly journals Teasing Apart the Role of the Ribosome and Molecular Chaperones in Cellular Protein Folding

2018 ◽  
Vol 114 (3) ◽  
pp. 414a
Author(s):  
Rayna M. Addabbo ◽  
Matthew D. Dalphin ◽  
Yue Liu ◽  
Miranda F. Mecha ◽  
Silvia Cavagnero
Keyword(s):  
Protein Folding ◽  
Molecular Chaperones ◽  
Cellular Protein

scholarly journals ER stress and development of type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Feyza Engin
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Adaptive Responses ◽  
Β Cell ◽  
Cellular Homeostasis ◽  
Unfolded Protein

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

scholarly journals Characterization of the endoplasmic reticulum–resident peroxidases GPx7 and GPx8 shows the higher oxidative activity of GPx7 and its linkage to oxidative protein folding

2020 ◽  
Vol 295 (36) ◽  
pp. 12772-12785 ◽  
Author(s):  
Shingo Kanemura ◽  
Elza Firdiani Sofia ◽  
Naoya Hirai ◽  
Masaki Okumura ◽  
Hiroshi Kadokura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Physiological Role ◽  
High Reactivity ◽  
Oxidation Activity ◽  
Formation Pathway ◽  
Oxidative Protein Folding ◽  
Redox Active ◽  
Protein Disulfide

Oxidative protein folding occurs primarily in the mammalian endoplasmic reticulum, enabled by a diverse network comprising more than 20 members of the protein disulfide isomerase (PDI) family and more than five PDI oxidases. Although the canonical disulfide bond formation pathway involving Ero1α and PDI has been well-studied so far, the physiological roles of the newly identified PDI oxidases, glutathione peroxidase-7 (GPx7) and -8 (GPx8), are only poorly understood. We here demonstrated that human GPx7 has much higher reactivity with H2O2 and hence greater PDI oxidation activity than human GPx8. The high reactivity of GPx7 is due to the presence of a catalytic tetrad at the redox-active site, which stabilizes the sulfenylated species generated upon the reaction with H2O2. Although it was previously postulated that GPx7 catalysis involved a highly reactive peroxidatic cysteine that can be sulfenylated by H2O2, we revealed that a resolving cysteine instead regulates the PDI oxidation activity of GPx7. We also determined that GPx7 formed complexes preferentially with PDI and P5 in H2O2-treated cells. Altogether, these results suggest that human GPx7 functions as an H2O2-dependent PDI oxidase in cells, whereas PDI oxidation may not be the central physiological role of human GPx8.

Role of Molecular Chaperones in Protein Folding

2010 ◽  
pp. 47-72 ◽  
Author(s):  
Kausik Chakraborty ◽  
Florian Georgescauld ◽  
Manajit Hayer-Hartl ◽  
F. Ulrich Hartl
Keyword(s):  
Protein Folding ◽  
Molecular Chaperones

scholarly journals Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy

2010 ◽  
Vol 2010 ◽  
pp. 1-19 ◽  
Author(s):  
Tom Verfaillie ◽  
Maria Salazar ◽  
Guillermo Velasco ◽  
Patrizia Agostinis
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Signal Transduction Pathway ◽  
Chemotherapeutic Agents ◽  
Cancer Therapies ◽  
Unfolded Protein ◽  
Adaptive Mechanisms ◽  
Intracellular Signal Transduction Pathway ◽  
Protein Response ◽  
Er Homeostasis

Different physiological and pathological conditions can perturb protein folding in the endoplasmic reticulum, leading to a condition known as ER stress. ER stress activates a complex intracellular signal transduction pathway, called unfolded protein response (UPR). The UPR is tailored essentially to reestablish ER homeostasis also through adaptive mechanisms involving the stimulation of autophagy. However, when persistent, ER stress can switch the cytoprotective functions of UPR and autophagy into cell death promoting mechanisms. Recently, a variety of anticancer therapies have been linked to the induction of ER stress in cancer cells, suggesting that strategies devised to stimulate its prodeath function or block its prosurvival function, could be envisaged to improve their tumoricidial action. A better understanding of the molecular mechanisms that determine the final outcome of UPR and autophagy activation by chemotherapeutic agents, will offer new opportunities to improve existing cancer therapies as well as unravel novel targets for cancer treatment.

The role of molecular chaperones in protein folding.

1995 ◽  
Vol 9 (15) ◽  
pp. 1559-1569 ◽  
Author(s):  
J P Hendrick ◽  
F U Hartl
Keyword(s):  
Protein Folding ◽  
Molecular Chaperones

scholarly journals Chaperone-mediated hierarchical control in targeting misfolded proteins to aggresomes

2011 ◽  
Vol 22 (18) ◽  
pp. 3277-3288 ◽  
Author(s):  
Xingqian Zhang ◽  
Shu-Bing Qian
Keyword(s):  
Protein Folding ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Hierarchical Control ◽  
Dominant Negative ◽  
Misfolded Proteins ◽  
Interacting Protein ◽  
Aggresome Formation

Protein misfolding is a common event in living cells. Molecular chaperones not only assist protein folding; they also facilitate the degradation of misfolded polypeptides. When the intracellular degradative capacity is exceeded, juxtanuclear aggresomes are formed to sequester misfolded proteins. Despite the well-established role of chaperones in both protein folding and degradation, how chaperones regulate the aggregation process remains controversial. Here we investigate the molecular mechanisms underlying aggresome formation in mammalian cells. Analysis of the chaperone requirements for the fate of misfolded proteins reveals an unexpected role of heat shock protein 70 (Hsp70) in promoting aggresome formation. This proaggregation function of Hsp70 relies on the interaction with the cochaperone ubiquitin ligase carboxyl terminal of Hsp70/Hsp90 interacting protein (CHIP). Disrupting Hsp70–CHIP interaction prevents the aggresome formation, whereas a dominant-negative CHIP mutant sensitizes the aggregation of misfolded protein. This accelerated aggresome formation also relies on the stress-induced cochaperone Bcl2-associated athanogene 3. Our results indicate that a hierarchy of cochaperone interaction controls different aspects of the intracellular protein triage decision, extending the function of Hsp70 from folding and degradation to aggregation.

scholarly journals ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

2021 ◽  
Vol 8 ◽  
Author(s):  
Venturina Stagni ◽  
Alessandra Ferri ◽  
Claudia Cirotti ◽  
Daniela Barilà
Keyword(s):  
Cell Fate ◽  
Ataxia Telangiectasia ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Premature Aging ◽  
Ataxia Telangiectasia Mutated ◽  
Atm Kinase ◽  
Cellular Environment ◽  
Key Factor

Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.

scholarly journals Androgen action in cell fate and communication during prostate development at single-cell resolution

Development ◽  
2020 ◽  
pp. dev.196048
Author(s):  
Dong-Hoon Lee ◽  
Adam W. Olson ◽  
Jinhui Wang ◽  
Won Kyung Kim ◽  
Jiaqi Mi ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Bud Formation ◽  
Master Regulators ◽  
Prostate Development ◽  
Dynamic Cell ◽  
Cell Signaling Networks

Androgens/androgen receptor (AR) mediated signaling pathways are essential for prostate development, morphogenesis, and regeneration. Specifically, stromal AR-signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were characterized in regulating prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation mesenchymal rather than epithelial cells dysregulates the expression of the master regulators and significantly impairs prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling as cellular niches controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.

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