scholarly journals SARS-CoV-2 Encodes a PPxY Late Domain Motif that is Known to Enhance Budding and Spread in Enveloped RNA Viruses

2020 ◽  
Author(s):  
Halim Maaroufi
Keyword(s):  
Viral Load ◽  
Molecular Mechanisms ◽  
Rna Viruses ◽  
Ubiquitin Ligases ◽  
High Viral Load ◽  
E3 Ubiquitin Ligases ◽  
Virus Budding ◽  
Novel Host ◽  
Escrt Complex ◽  
Disordered Loop

ABSTRACTCurrently, the global COVID-19 (Coronavirus Disease-2019) pandemic is affecting the health and/or socioeconomic life of almost each people in the world. Finding vaccines and therapeutics is urgent but without forgetting to elucidate the molecular mechanisms that allow some viruses to become dangerous for humans. Here, analysis of all proteins of SARS-CoV-2 revealed a unique PPxY Late (L) domain motif 25PPAY28 in spike protein inside hot disordered loop predicted subject to phosphorylation and binding. It was demonstrated in enveloped RNA viruses that PPxY motif recruits Nedd4 E3 ubiquitin ligases and ultimately the ESCRT complex to enhance virus budding and release that means a high viral load, hence facilitating new infections. Note that PPxY motif is not present in proteins of SARS-CoV. This suggests that PPxY motif by its role in enhancing the viral load could explain why SARS-CoV-2 is more contagious than SARS-CoV. Of course, after the experimental verifications showing that PPxY motif plays the same role as reported for other enveloped RNA viruses, it could become an interesting target for the development of novel host-oriented antivirals therapeutics for preventing S protein to recruit Nedd4 E3 ubiquitin ligases partners.

scholarly journals How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases

2021 ◽  
Vol 22 (4) ◽  
pp. 2078
Author(s):  
Ji An Kang ◽  
Young Joo Jeon
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Molecular Mechanisms ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
E3 Ubiquitin Ligases ◽  
Quantity Control

The endoplasmic reticulum (ER) is an interconnected organelle that plays fundamental roles in the biosynthesis, folding, stabilization, maturation, and trafficking of secretory and transmembrane proteins. It is the largest organelle and critically modulates nearly all aspects of life. Therefore, in the endoplasmic reticulum, an enormous investment of resources, including chaperones and protein folding facilitators, is dedicated to adequate protein maturation and delivery to final destinations. Unfortunately, the folding and assembly of proteins can be quite error-prone, which leads to the generation of misfolded proteins. Notably, protein homeostasis, referred to as proteostasis, is constantly exposed to danger by flows of misfolded proteins and subsequent protein aggregates. To maintain proteostasis, the ER triages and eliminates terminally misfolded proteins by delivering substrates to the ubiquitin–proteasome system (UPS) or to the lysosome, which is termed ER-associated degradation (ERAD) or ER-phagy, respectively. ERAD not only eliminates misfolded or unassembled proteins via protein quality control but also fine-tunes correctly folded proteins via protein quantity control. Intriguingly, the diversity and distinctive nature of E3 ubiquitin ligases determine efficiency, complexity, and specificity of ubiquitination during ERAD. ER-phagy utilizes the core autophagy machinery and eliminates ERAD-resistant misfolded proteins. Here, we conceptually outline not only ubiquitination machinery but also catalytic mechanisms of E3 ubiquitin ligases. Further, we discuss the mechanistic insights into E3 ubiquitin ligases involved in the two guardian pathways in the ER, ERAD and ER-phagy. Finally, we provide the molecular mechanisms by which ERAD and ER-phagy conduct not only protein quality control but also protein quantity control to ensure proteostasis and subsequent organismal homeostasis.

scholarly journals SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability

2021 ◽  
Vol 22 (10) ◽  
pp. 5391
Author(s):  
Ya-Chu Chang ◽  
Marissa K. Oram ◽  
Anja-Katrin Bielinsky
Keyword(s):  
Dna Repair ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Ubiquitin Ligases ◽  
Genotoxic Stress ◽  
E3 Ubiquitin Ligases ◽  
Sumo Proteases ◽  
Stalled Replication Forks ◽  
Spatiotemporal Control ◽  
Maintain Genome Stability

Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA repair, replication, mitosis, and transcription. They operate during unperturbed conditions and in response to challenges, such as genotoxic stress. These E3 ubiquitin ligases modify their target substrates by catalyzing ubiquitin chains that form different linkages, resulting in proteolytic or non-proteolytic outcomes. Often, STUbLs function in compartmentalized environments, such as the nuclear envelope or kinetochore, and actively aid in nuclear relocalization of damaged DNA and stalled replication forks to promote DNA repair or fork restart. Furthermore, STUbLs reside in the same vicinity as SUMO proteases and deubiquitinases (DUBs), providing spatiotemporal control of their targets. In this review, we focus on the molecular mechanisms by which STUbLs help to maintain genome stability across different species.

Update in management of hepatitis B in pregnancy and prevention of mother to child hepatitis B transmission

2018 ◽  
Vol 1 (3) ◽  
pp. 1-8
Author(s):  
Naichaya Chamroonkul
Keyword(s):  
Chronic Hepatitis ◽  
Viral Load ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
High Viral Load ◽  
World Population ◽  
Hepatitis B Infection ◽  
Mother To Child Transmission ◽  
Child Transmission ◽  
Mother To Child

Even with two decades of widespread using hepatitis B vaccination, chronic hepatitis B remains a major global health problem. In Thailand, the prevalence of chronic hepatitis B infection was down from 8 - 10% in last decade to 5% recently. Failure to control mother to child transmission is one of the important barriers to the total elimination of hepatitis B infection from world population. In the majority, vertical transmission can be prevented with a universal screening program, immunoprophylaxis by administration of hepatitis B vaccine and hepatitis B immunoglobulin (HBIg) for babies born to mothers with HBV. However, in mothers with a high viral load, the chance of immunoprophylaxis failure remains high. To date, there are standard recommendations by all international liver societies including AASLD, EASL and APASL suggest introducing an antiviral agent during the third trimester to CHB pregnant women with a high viral load. Previous US FDA pregnancy category B agents such as Tenofovir and Telbivudine are allowed through all trimesters of pregnancy and are effective for prevention of mother to child transmission. Breastfeeding for patients who receive antiviral agents can be allowed after a risk-benefit discussion with the patient and family.

Regulation of Epithelial-Mesenchymal Transition by E3 Ubiquitin Ligases and Deubiquitinase in Cancer

2016 ◽  
Vol 16 (2) ◽  
pp. 110-118 ◽  
Author(s):  
Yasumichi Inoue ◽  
Yuka Itoh ◽  
Koichi Sato ◽  
Fumihiro Kawasaki ◽  
Chihiro Sumita ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Mesenchymal Transition

scholarly journals Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1015
Author(s):  
Utsa Bhaduri ◽  
Giuseppe Merla
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Genetic Disorders ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Post Translational Modification ◽  
Disease Biology ◽  
The Future

Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

scholarly journals Adapting the role of handheld echocardiography during the COVID-19 pandemic: A practical guide

Perfusion ◽  
2021 ◽  
pp. 026765912098653
Author(s):  
Hafiz Naderi ◽  
Shaun Robinson ◽  
Martin J Swaans ◽  
Nina Bual ◽  
Wing-See Cheung ◽  
...  
Keyword(s):  
Viral Load ◽  
Potential Role ◽  
Assessment Tool ◽  
High Viral Load ◽  
First Line ◽  
Scanning Time ◽  
Contagious Disease ◽  
Core Dataset ◽  
Clinical Questions

The COVID-19 pandemic has altered our approach to inpatient echocardiography delivery. There is now a greater focus to address key clinical questions likely to make an immediate impact in management, particularly during the period of widespread infection. Handheld echocardiography (HHE) can be used as a first-line assessment tool, limiting scanning time and exposure to high viral load. This article describes a potential role for HHE during a pandemic. We propose a protocol with a reporting template for a focused core dataset necessary in delivering an acute echocardiography service in the setting of a highly contagious disease, minimising risk to the operator. We cover the scenarios typically encountered in the acute cardiology setting and how an expert trained echocardiography team can identify such pathologies using a limited imaging format and include cardiac presentations encountered in those patients acutely unwell with COVID-19.

scholarly journals TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 820
Author(s):  
Lorena Kumarasinghe ◽  
Lu Xiong ◽  
Maria Adelaida Garcia-Gimeno ◽  
Elisa Lazzari ◽  
Pascual Sanz ◽  
...  
Keyword(s):  
Common Ancestor ◽  
Genetic Diseases ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Lafora Disease ◽  
C Terminus ◽  
Rare Genetic Diseases ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Ring E3

Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

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