scholarly journals Precise temporal regulation of post-transcriptional repressors is required for an orderly Drosophila maternal-to-zygotic transition

2019 ◽  
Author(s):  
Wen Xi Cao ◽  
Sarah Kabelitz ◽  
Meera Gupta ◽  
Eyan Yeung ◽  
Sichun Lin ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Gene Products ◽  
Transcriptional Repressors ◽  
Protein Coding ◽  
Temporal Regulation ◽  
Maternal Contribution ◽  
Maternal To Zygotic Transition ◽  
Zygotic Gene ◽  
Ubiquitin Proteasome ◽  
Coding Capacity

SUMMARYIn animal embryos the maternal-to-zygotic transition (MZT) hands developmental control from maternal to zygotic gene products. We show that the maternal proteome represents over half of the protein coding capacity of the Drosophila melanogaster genome and that 2% of this proteome is rapidly degraded during the MZT. Cleared proteins include the post-transcriptional repressors Cup, Trailer hitch (TRAL), Maternal expression at 31B (ME31B), and Smaug (SMG). While the ubiquitin-proteasome system is necessary for clearance of all four repressors, distinct E3 ligase complexes target them: the C-terminal to Lis1 Homology (CTLH) complex targets Cup, TRAL and ME31B for degradation early in the MZT; the Skp/Cullin/F-box-containing (SCF) complex targets SMG at the end of the MZT. Deleting the C-terminal 233 amino acids of SMG makes the protein immune to degradation. We show that artificially persistent SMG downregulates the zygotic re-expression of mRNAs whose maternal contribution is cleared by SMG. Thus, clearance of SMG permits an orderly MZT.

The Ubiquitin-Proteasome System in the Maternal-to-Zygotic Transition

2013 ◽  
Vol 30 (3) ◽  
pp. 79-85 ◽  
Author(s):  
Seung-Wook Shin ◽  
Shigeo Murata ◽  
Kazuya Matsumoto
Keyword(s):  
Ubiquitin Proteasome System ◽  
Maternal To Zygotic Transition ◽  
Ubiquitin Proteasome

scholarly journals Large-scale RNAi screening uncovers new therapeutic targets in the human parasite Schistosoma mansoni

2020 ◽  
Author(s):  
Jipeng Wang ◽  
Carlos Paz ◽  
Gilda Padalino ◽  
Avril Coghlan ◽  
Zhigang Lu ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Large Scale ◽  
Ubiquitin Proteasome System ◽  
Mammalian Host ◽  
Protein Coding ◽  
Major Barrier ◽  
Stem Cell Maintenance ◽  
Ubiquitin Proteasome ◽  
Protein Kinase Signaling

Schistosomes kill 250,000 people every year and are responsible for serious morbidity in 240 million of the world's poorest people. Despite their profound global impact, only a single drug (praziquantel) is available to treat schistosomiasis, highlighting the need to better understand schistosome biology to drive the development of a new generation of therapeutics. A major barrier to this goal is the paucity of large-scale datasets exploring schistosome gene function. Here, we describe the first large-scale RNA interference screen in adult Schistosoma mansoni examining the function of over 2000 genes representing approximately 20 percent of the protein coding genome. More than 250 genes were found to have phenotypes affecting neuromuscular function, tissue integrity, stem cell maintenance, and parasite survival. Leveraging these data, we bioinformatically prioritized several compounds with in vitro activity against parasites and validated p97, a component of the ubiquitin proteasome system, as a drug target in the worm. We further reveal a potentially druggable protein kinase-signaling module involving the TAO and STK25 kinases that are essential for maintaining the transcription of muscle-specific mRNAs. Importantly, loss of either of these kinases results in paralysis and death of schistosomes following surgical transplantation into a mammalian host. We anticipate this work will invigorate studies into the biology of these poorly studied organisms and expedite the development of new therapeutics to treat an important neglected tropical disease.

scholarly journals Precise Temporal Regulation of Post-transcriptional Repressors Is Required for an Orderly Drosophila Maternal-to-Zygotic Transition

Cell Reports ◽  
2020 ◽  
Vol 31 (12) ◽  
pp. 107783 ◽  
Author(s):  
Wen Xi Cao ◽  
Sarah Kabelitz ◽  
Meera Gupta ◽  
Eyan Yeung ◽  
Sichun Lin ◽  
...  
Keyword(s):  
Transcriptional Repressors ◽  
Temporal Regulation ◽  
Maternal To Zygotic Transition

Pou5f1 Transcription Factor Controls Zygotic Gene Activation In Vertebrates

Science ◽  
2013 ◽  
Vol 341 (6149) ◽  
pp. 1005-1009 ◽  
Author(s):  
Manuel Leichsenring ◽  
Julia Maes ◽  
Rebecca Mössner ◽  
Wolfgang Driever ◽  
Daria Onichtchouk
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Gene Activation ◽  
Gene Products ◽  
Developmental Control ◽  
Zygotic Transcription ◽  
Maternal To Zygotic Transition ◽  
Zygotic Gene ◽  
Zygotic Gene Activation ◽  
Maternal Gene

The development of multicellular animals is initially controlled by maternal gene products deposited in the oocyte. During the maternal-to-zygotic transition, transcription of zygotic genes commences, and developmental control starts to be regulated by zygotic gene products. In Drosophila, the transcription factor Zelda specifically binds to promoters of the earliest zygotic genes and primes them for activation. It is unknown whether a similar regulation exists in other animals. We found that zebrafish Pou5f1, a homolog of the mammalian pluripotency transcription factor Oct4, occupies SOX-POU binding sites before the onset of zygotic transcription and activates the earliest zygotic genes. Our data position Pou5f1 and SOX-POU sites at the center of the zygotic gene activation network of vertebrates and provide a link between zygotic gene activation and pluripotency control.

scholarly journals The E2 Marie Kondo and the CTLH E3 ligase clear deposited RNA binding proteins during the maternal-to-zygotic transition

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Michael Zavortink ◽  
Lauren N Rutt ◽  
Svetlana Dzitoyeva ◽  
Jesslyn C Henriksen ◽  
Chloe Barrington ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Substrate Recognition ◽  
Ubiquitin Proteasome System ◽  
Structure Modeling ◽  
Animal Development ◽  
Maternal To Zygotic Transition ◽  
Ubiquitin Proteasome ◽  
Zygotic Genome

The maternal-to-zygotic transition (MZT) is a conserved step in animal development, where control is passed from the maternal to the zygotic genome. Although the MZT is typically considered from its impact on the transcriptome, we previously found that three maternally deposited Drosophila RNA-binding proteins (ME31B, Trailer Hitch [TRAL], and Cup) are also cleared during the MZT by unknown mechanisms. Here, we show that these proteins are degraded by the ubiquitin-proteasome system. Marie Kondo, an E2 conjugating enzyme, and the E3 CTLH ligase are required for the destruction of ME31B, TRAL, and Cup. Structure modeling of the Drosophila CTLH complex suggests that substrate recognition is different than orthologous complexes. Despite occurring hours earlier, egg activation mediates clearance of these proteins through the Pan Gu kinase, which stimulates translation of Kdo mRNA. Clearance of the maternal protein dowry thus appears to be a coordinated, but as-yet underappreciated, aspect of the MZT.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 ◽  
pp. 173-186 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Proteolytic Enzymes ◽  
Cathepsin L ◽  
Ubiquitin Proteasome System ◽  
Complete Breakdown ◽  
Skeletal Muscle Proteins ◽  
Ubiquitin Proteasome ◽  
Tripeptidyl Peptidase Ii ◽  
F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 (1) ◽  
pp. 173 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome

Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome

2020 ◽  
Author(s):  
Jon Uranga ◽  
Lukas Hasecke ◽  
Jonny Proppe ◽  
Jan Fingerhut ◽  
Ricardo A. Mata
Keyword(s):  
Active Site ◽  
Boronic Acid ◽  
Computational Study ◽  
Ubiquitin Proteasome System ◽  
Bayesian Optimization ◽  
Inhibition Mechanism ◽  
20S Proteasome ◽  
Acid Base ◽  
Ubiquitin Proteasome ◽  
Infection Cycles

The 20S Proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells as well as in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome, an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy and boronic acid containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics and Bayesian optimization of non-bonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach to the reevaluation of non-bonded potentials making use of QM/MM dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the inhibitor.

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