scholarly journals Sperm acrosome overgrowth and infertility in mice lacking chromosome 18 pachytene piRNA

2020 ◽  
Author(s):  
Heejin Choi ◽  
Zhengpin Wang ◽  
Jurrien Dean
Keyword(s):  
Ubiquitin Proteasome System ◽  
Genome Integrity ◽  
Male Gametogenesis ◽  
Pirna Cluster ◽  
Ubiquitin Proteasome ◽  
Non Coding Rnas ◽  
Shock Proteins ◽  
And Function ◽  
Golgi Network

AbstractpiRNAs are germline-specific, small non-coding RNAs required to maintain genome integrity and preserve RNA homeostasis during male gametogenesis. In murine adult testes, the highest levels of piRNAs are present in the pachytene stage of meiosis, but their mode of action and function remains incompletely understood. We previously reported that BTBD18 binds to 50 pachytene piRNA-producing loci. Here we show that spermatozoa in gene-edited mice lacking a BTBD18 targeted pachytene piRNA cluster on Chr18 have severe sperm head dysmorphology, poor motility, impaired acrosome exocytosis and are sterile. The absence of Chr18 piRNA results in an imbalance of heat shock proteins associated with renaturing proteins and the ubiquitin-proteasome system involved with protein degradation. The mutant phenotype arises from aberrant formation of proacrosomal vesicles, distortion of the trans-Golgi network, and up-regulation of GOLGA2 associated with acrosome dysgenesis. Collectively, our findings reveal central role of pachytene piRNAs in controlling spermiogenesis and male fertility.

scholarly journals Sperm acrosome overgrowth and infertility in mice lacking chromosome 18 pachytene piRNA

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009485
Author(s):  
Heejin Choi ◽  
Zhengpin Wang ◽  
Jurrien Dean
Keyword(s):  
Zona Pellucida ◽  
Male Fertility ◽  
Sperm Head ◽  
Genome Integrity ◽  
Male Gametogenesis ◽  
Pirna Cluster ◽  
Non Coding Rnas ◽  
And Function ◽  
Golgi Network

piRNAs are small non-coding RNAs required to maintain genome integrity and preserve RNA homeostasis during male gametogenesis. In murine adult testes, the highest levels of piRNAs are present in the pachytene stage of meiosis, but their mode of action and function remain incompletely understood. We previously reported that BTBD18 binds to 50 pachytene piRNA-producing loci. Here we show that spermatozoa in gene-edited mice lacking a BTBD18 targeted pachytene piRNA cluster on Chr18 have severe sperm head dysmorphology, poor motility, impaired acrosome exocytosis, zona pellucida penetration and are sterile. The mutant phenotype arises from aberrant formation of proacrosomal vesicles, distortion of the trans-Golgi network, and up-regulation of GOLGA2 transcripts and protein associated with acrosome dysgenesis. Collectively, our findings reveal central role of pachytene piRNAs in controlling spermiogenesis and male fertility.

scholarly journals It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Antonella Tramutola ◽  
Fabio Di Domenico ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
D. Allan Butterfield
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Ubiquitin Proteasome System ◽  
Oxidative Modification ◽  
Age Related ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function ◽  
Cellular Components

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

scholarly journals Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

2020 ◽  
Vol 21 (17) ◽  
pp. 5962 ◽  
Author(s):  
Takashi Shiromizu ◽  
Mizuki Yuge ◽  
Kousuke Kasahara ◽  
Daishi Yamakawa ◽  
Takaaki Matsui ◽  
...  
Keyword(s):  
Essential Role ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
E3 Ubiquitin Ligases ◽  
Complex Disorders ◽  
Ciliary Function ◽  
Ubiquitin Proteasome ◽  
And Function

Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause various diseases, including cancer and ciliopathies, which are complex disorders caused by mutations in genes regulating ciliary function. The structure and function of cilia are dynamically regulated through various mechanisms, among which E3 ubiquitin ligases and deubiquitinases play crucial roles. These enzymes regulate the degradation and stabilization of ciliary proteins through the ubiquitin–proteasome system. In this review, we briefly highlight the role of cilia in ciliopathy and cancer; describe the roles of E3 ubiquitin ligases and deubiquitinases in ciliogenesis, ciliopathy, and cancer; and highlight some of the E3 ubiquitin ligases and deubiquitinases that are potential therapeutic targets for these disorders.

scholarly journals Tearin' Up My Heart: Proteolysis in the Cardiac Sarcomere

2011 ◽  
Vol 286 (12) ◽  
pp. 9929-9934 ◽  
Author(s):  
Andrea L. Portbury ◽  
Monte S. Willis ◽  
Cam Patterson
Keyword(s):  
Cardiovascular Health ◽  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
Cardiac Sarcomere ◽  
Ubiquitin Proteasome ◽  
Health And Disease ◽  
The Individual ◽  
And Function ◽  
Calpain System

Proteolysis within the cardiac sarcomere is a constantly evolving area of research. Three major pathways of proteolysis have been identified as being active within the cardiac sarcomere, namely the ubiquitin-proteasome system, autophagy, and the calpain system. The role of ubiquitin-proteasome system-mediated proteolysis in cardiovascular health and disease has been known for some time; however, it is now apparent that other proteolytic systems also aid in the stabilization of cardiac sarcomere structure and function. This minireview focuses on the individual as well as cooperative involvement of each of these three major pathways of proteolysis within the cardiac sarcomere.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

scholarly journals Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

2013 ◽  
Vol 31 (9) ◽  
pp. 1231-1238 ◽  
Author(s):  
Lindsey N. Micel ◽  
John J. Tentler ◽  
Peter G. Smith ◽  
Gail S. Eckhardt
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Regulation ◽  
Ubiquitin Chain ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Enzyme Families ◽  
And Function

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

scholarly journals Non-Coding RNA in Pancreas and β-Cell Development

2018 ◽  
Vol 4 (4) ◽  
pp. 41 ◽  
Author(s):  
Wilson K. M. Wong ◽  
Anja E. Sørensen ◽  
Mugdha V. Joglekar ◽  
Anand A. Hardikar ◽  
Louise T. Dalgaard
Keyword(s):  
Cell Function ◽  
Islet Cells ◽  
Current Knowledge ◽  
Cell Development ◽  
Pancreas Development ◽  
Β Cell ◽  
Neighboring Gene ◽  
Non Coding Rnas ◽  
And Function

In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.

scholarly journals Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Author(s):  
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Atrophy ◽  
Late Onset ◽  
Oral Treatment ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Functional Study ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Ubiquitin Proteasome ◽  
And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

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