scholarly journals The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6065
Author(s):  
Jun Goto ◽  
Yoichiro Otaki ◽  
Tetsu Watanabe ◽  
Masafumi Watanabe

Despite advances in medicine, cardiac disease remains an increasing health problem associated with a high mortality rate. Maladaptive cardiac remodeling, such as cardiac hypertrophy and fibrosis, is a risk factor for heart failure; therefore, it is critical to identify new therapeutic targets. Failing heart is reported to be associated with hyper-ubiquitylation and impairment of the ubiquitin–proteasome system, indicating an importance of ubiquitylation in the development of cardiac disease. Ubiquitylation is a post-translational modification that plays a pivotal role in protein function and degradation. In 1995, homologous to E6AP C-terminus (HECT) type E3 ligases were discovered. E3 ligases are key enzymes in ubiquitylation and are classified into three families: really interesting new genes (RING), HECT, and RING-between-RINGs (RBRs). Moreover, 28 HECT-type E3 ligases have been identified in human beings. It is well conserved in evolution and is characterized by the direct attachment of ubiquitin to substrates. HECT-type E3 ligase is reported to be involved in a wide range of human diseases and health. The role of HECT-type E3 ligases in the development of cardiac diseases has been uncovered in the last decade. There are only a few review articles summarizing recent advancements regarding HECT-type E3 ligase in the field of cardiac disease. This study focused on cardiac remodeling and described the role of HECT-type E3 ligases in the development of cardiac disease. Moreover, this study revealed that the current knowledge could be exploited for the development of new clinical therapies.

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 98 ◽  
Author(s):  
Paola Infante ◽  
Ludovica Lospinoso Severini ◽  
Flavia Bernardi ◽  
Francesca Bufalieri ◽  
Lucia Di Marcotullio

Hedgehog signalling (Hh) is a developmental conserved pathway strongly involved in cancers when deregulated. This important pathway is orchestrated by numerous regulators, transduces through distinct routes and is finely tuned at multiple levels. In this regard, ubiquitylation processes stand as essential for controlling Hh pathway output. Although this post-translational modification governs proteins turnover, it is also implicated in non-proteolytic events, thereby regulating the most important cellular functions. The HECT E3 ligase Itch, well known to control immune response, is emerging to have a pivotal role in tumorigenesis. By illustrating Itch specificities on Hh signalling key components, here we review the role of this HECT E3 ubiquitin ligase in suppressing Hh-dependent tumours and explore its potential as promising target for innovative therapeutic approaches.


Author(s):  
Fabienne Podieh ◽  
Peter L. Hordijk

Cullin3-based ubiquitin E3 ligases induce ubiquitination of substrates leading to their proteasomal or lysosomal degradation. BTB proteins serve as adaptors by binding to Cullin3 and recruiting substrate proteins, which enables specific recognition of a broad spectrum of targets. Hence, Cullin3 and its adaptors are involved in myriad cellular processes and organ functions. Cullin3-based ubiquitin E3 ligase complexes target small GTPases of the Rho subfamily, which are key regulators of cytoskeletal dynamics and cell adhesion. In this mini review, we discuss recent insights in Cullin3-mediated regulation of Rho GTPases and their impact on cellular function and disease. Intriguingly, upstream regulators of Rho GTPases are targeted by Cullin3 complexes as well. Thus, Rho GTPase signaling is regulated by Cullin3 on multiple levels. In addition, we address current knowledge of Cullin3 in regulating vascular function, focusing on its prominent role in endothelial barrier function, angiogenesis and the regulation of blood pressure.


Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1494 ◽  
Author(s):  
Antonio Magán-Fernández ◽  
Sarmad Muayad Rasheed Al-Bakri ◽  
Francisco O’Valle ◽  
Cristina Benavides-Reyes ◽  
Francisco Abadía-Molina ◽  
...  

Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil response to a wide range of stimuli, such as pathogens, host-derived mediators and drugs. Neutrophils can remain functional after NET formation and are important for periodontal homeostasis. Periodontitis is an inflammatory multifactorial disease caused by a dysbiosis state between the gingival microbiome and the immune response of the host. The pathogenesis of periodontitis includes an immune-inflammatory component in which impaired NET formation and/or elimination can be involved, contributing to an exacerbated inflammatory reaction and to the destruction of gingival tissue. In this review, we summarize the current knowledge about the role of NETs in the pathogenesis of periodontitis.


Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1648
Author(s):  
Daniel Liedtke ◽  
Christine Hofmann ◽  
Franz Jakob ◽  
Eva Klopocki ◽  
Stephanie Graser

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.


2013 ◽  
Vol 59 (8) ◽  
pp. 1166-1174 ◽  
Author(s):  
Fina Lovren ◽  
Subodh Verma

BACKGROUND Endothelial dysfunction is an early event in the development and progression of a wide range of cardiovascular diseases. Various human studies have identified that measures of endothelial dysfunction may offer prognostic information with respect to vascular events. Microparticles (MPs) are a heterogeneous population of small membrane fragments shed from various cell types. The endothelium is one of the primary targets of circulating MPs, and MPs isolated from blood have been considered biomarkers of vascular injury and inflammation. CONTENT This review summarizes current knowledge of the potential functional role of circulating MPs in promoting endothelial dysfunction. Cells exposed to different stimuli such as shear stress, physiological agonists, proapoptotic stimulation, or damage release MPs, which contribute to endothelial dysfunction and the development of cardiovascular diseases. Numerous studies indicate that MPs may trigger endothelial dysfunction by disrupting production of nitric oxide release from vascular endothelial cells and subsequently modifying vascular tone. Circulating MPs affect both proinflammatory and proatherosclerotic processes in endothelial cells. In addition, MPs can promote coagulation and inflammation or alter angiogenesis and apoptosis in endothelial cells. SUMMARY MPs play an important role in promoting endothelial dysfunction and may prove to be true biomarkers of disease state and progression.


Author(s):  
Samuel Torvend

Luther not only wrote about charity and social ethics throughout much of his life; he also experienced the conditions that were the object of Christian generosity and ethical reflection. This essay suggests that his study of the Bible and Church Fathers was not the only source of Luther’s writings and revolutionary programs. His experience of deprivation as a child and a monk, his encounters with the homeless poor of Wittenberg, and his observation of corrupt business practices and failed political leadership played significant roles in his sensitivity to the scriptures and the history of ecclesial care for the poor. The rise of social history and the use of social scientific methods have drawn attention to the economic, political, and social context in which Luther lived and to which he responded throughout his life. The reformer’s works on charity and social ethics did not emerge in a vacuum. His initial public foray focused on the “spiritual economy” of the late medieval church, which discriminated against many of Luther’s poor parishioners. While the Ninety-Five Theses raised serious questions about the sacrament of penance, the role of indulgences, and the authority of the pope, the text also reveals Luther’s early concern for the poor, who were frightened into buying spiritual favors for themselves or their dead relatives. In addition to theological problems, Luther recognized the ethical dimension of this large-scale sales campaign that benefited archbishops and the Vatican treasury. Luther’s rediscovery of the Pauline teaching on justification by grace alone reoriented Christians toward life in this world. Rather than spend effort or money on spiritual exercises that might win one God’s favor in the afterlife, human energies could be directed toward alleviating present suffering. A dialectical thinker, Luther insisted on holding together two seemingly irreconcilable claims, two disparate texts, two discordant images in order to raise the question: How is one related to the other? His teaching on justification claims that God always advances toward a suffering humanity first and that this advance is revealed with utter clarity in the person and work of Jesus Christ, who incarnates God’s desire to free human beings from the deathly presence of anxious religion and give them “life, health, and salvation.” But such freedom must be used for the good of one’s neighbor who suffers within the economic, political, and social fabric of life. The advance of God, who is mercy and grace, continues into the world through Christ and his body. This essay suggests that while Luther animated significant contributions to biblical studies and theology, a body of ethical teaching has been harder to discern among his followers. Perhaps this hesitancy arose out of fear that an emphasis on ethics would be construed as a lapse into what Luther called “works righteousness.” This essay considers a number of the ethical questions and crises that faced Luther, which have not subsided and ask for contemporary investigation. A remarkable achievement of Luther’s reform was a revolutionary change in social assistance. The monastic communities of western Europe had long served as centers of hospitality and charity, and the order in which the young Luther made his vows was a reforming order committed to austerity of life and care for the urban poor. For theological reasons, Luther promoted the suppression of the monasteries and vilified the mendicant orders, but this left a gap in care for the growing population of homeless peasants seeking work in urban centers. The reform of social assistance undertaken in the small “Lutheran” town of Leisnig, Germany, in the early 16th century would become the model for many church orders throughout Germany and Scandinavia, influencing today’s state-run and tax-funded assistance to needy families. Recently, ethicists and Luther scholars have reassessed his reform of charity to ask how the reformer’s social teaching might support engagement with a wide range of present-day social movements. Increased study of Luther’s social writings and the study of evangelical “church orders,” previously marginalized in the academy, offers promising avenues for continued research. This essay also compares three forms of charity—Lutheran, Roman Catholic, and Reformed—illustrating the symbiotic relationship between social ethics and theology and underscoring the role of theological priorities in the conceptualization of social assistance. Finally, this essay considers Luther’s writings on social ethics. Frequently, interpreters of this focus on “faith active in love,” or the utility of his distinction between two kingdoms or governments. Such studies offer a biblical or theological grounding for Lutheran ethics yet frequently overlook the actual crises or practices he encountered. Luther was not a “systematic” theologian, and one must search through his many writings to discover his “ethical” teachings. Luther scholars and historians of social ethics are increasingly interested in the specific ethical questions he was asked to discuss by those who had accepted his reform. The growing popularity of his reform movement and the seismic shift in Christian thought and practice it animated left Luther little time to construct a well-ordered corpus of social teaching, yet many of his concerns are vitally alive in the world today albeit within a different context. Many of his concerns were enlightened by his study of scripture, in which he recognized a mirror of his own turbulent era.


Glycobiology ◽  
2020 ◽  
Author(s):  
Kaitlyn A Dorsett ◽  
Michael P Marciel ◽  
Jihye Hwang ◽  
Katherine E Ankenbauer ◽  
Nikita Bhalerao ◽  
...  

Abstract The ST6GAL1 sialyltransferase, which adds α2–6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress, and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics. However, despite the burgeoning interest in the role of ST6GAL1 in the phenotypic features of tumor cells, insufficient attention has been paid to the molecular mechanisms responsible for ST6GAL1 upregulation during neoplastic transformation. Evidence suggests that these mechanisms are multifactorial, encompassing genetic, epigenetic, transcriptional, and post-translational regulation. The purpose of this review is to summarize current knowledge regarding the molecular events that drive enriched ST6GAL1 expression in cancer cells.


BMJ Open ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. e037217
Author(s):  
Stijntje Willemijn Dijk ◽  
Edwin Johan Duijzer ◽  
Matthias Wienold

ObjectivesTo identify the scope of active patient involvement in medical education, addressing the current knowledge gaps relating to rationale and motivation for involvement, recruitment and preparation, roles, learning outcomes and key procedural contributors.MethodsThe authors performed a systematic search of the PubMed database of publications between 2003 and 2018. Original studies in which patients take on active roles in the development, delivery or evaluation of undergraduate medical education and written in English were eligible for inclusion. Included studies’ references were searched for additional articles. Quality of papers was assessed using the Mixed Methods Appraisal Tool.Results49 articles were included in the review. Drivers for patient involvement included policy requirements and patients’ own motivations to contribute to society and learning. Patients were engaged in a variety of educational settings in and outside of the hospital. The vast majority of studies describe patients taking on the role of a patient teacher and formative assessor. More recent studies suggest that patients are increasingly involved in course and curriculum development, student selection and summative assessment. The new body of empirical evidence shows the wide range of learning objectives was pursued through patient participation, including competencies as professional, communicator, collaborator, leader and health advocate, but not scholar. Measures to support sustainable patient involvement included longitudinal institutional incorporation, patient recruitment and/or training, resource support and clear commitment by faculty. The importance and advantages of patient involvement were highlighted by students, faculty and patients themselves; however, organisations must continue to consider, monitor and take steps to mitigate any potential harms to patients and students.DiscussionThis systematic review provides new knowledge and practical insights to physicians and faculty on how to incorporate active patient involvement in their institutions and daily practice, and provides suggested action points to patient organisations wishing to engage in medical education.


2016 ◽  
Vol 43 (6) ◽  
pp. 553 ◽  
Author(s):  
Caroline A. Brocious ◽  
Uwe G. Hacke

Progress has been made in linking water transport in leaves with anatomical traits. However, most of our current knowledge about these links is based on studies that sampled phylogenetically distant species and covered a wide range of leaf size and morphology. Here we studied covariation of leaf anatomical traits and hydraulic capacity in five closely related hybrid poplar genotypes. Variation in stomatal conductance and leaf hydraulic conductance was not linked to vein density or other anatomical lamina properties. A strong correlation was found between stomatal conductance and the transport capacity of the petiole, estimated from the diameter and number of xylem vessels. An inverse relationship existed between leaf size and major vein density. The role of bundle sheath extensions is discussed. Our data suggests that petiole xylem is an important predictor of gas exchange capacity in poplar leaves.


2010 ◽  
Vol 15 (10) ◽  
pp. 1220-1228 ◽  
Author(s):  
Jeffrey G. Marblestone ◽  
K. G. Suresh Kumar ◽  
Michael J. Eddins ◽  
Craig A. Leach ◽  
David E. Sterner ◽  
...  

The ubiquitin-proteasome system is central to the regulation of numerous cellular events, and dysregulation may lead to disease pathogenesis. E3 ubiquitin ligases typically function in concert with E1 and E2 enzymes to recruit specific substrates, thereby coordinating their ubiquitylation and subsequent proteasomal degradation or cellular activity. E3 ligases have been implicated in a wide range of pathologies, and monitoring their activity in a rapid and cost-effective manner would be advantageous in drug discovery. The relative lack of high-throughput screening (HTS)–compliant E3 ligase assays has significantly hindered the discovery of E3 inhibitors. Herein, the authors describe a novel HTS-compliant E3 ligase assay platform that takes advantage of a ubiquitin binding domain’s inherent affinity for polyubiquitin chains, permitting the analysis of ubiquitin chain formation in an E3 ligase-dependent manner. This assay has been used successfully with members of both the RING and HECT families, demonstrating the platform’s broad utility for analyzing a wide range of E3 ligases. The utility of the assay platform is demonstrated by the identification of inhibitors of the E3 ligase CARP2. As the number of E3 ligases associated with various disease states increases, the ability to quantitate the activity of these enzymes in an expeditious manner becomes imperative in drug discovery.


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