Halofuginone triggers a transcriptional program centered on ribosome biogenesis and function in honey bees

Gene expression is an essential process for cellular growth, proliferation, and differentiation. The transcription of protein-coding genes and non-coding loci depends on RNA polymerases. Interestingly, numerous loci encode long non-coding (lnc)RNA transcripts that are transcribed by RNA polymerase II (RNAPII) and fine-tune the RNA metabolism. The nucleolus is a prime example of how different lncRNA species concomitantly regulate gene expression by facilitating the production and processing of ribosomal (r)RNA for ribosome biogenesis. Here, we summarise the current findings on how RNAPII influences nucleolar structure and function. We describe how RNAPII-dependent lncRNA can both promote nucleolar integrity and inhibit ribosomal (r)RNA synthesis by modulating the availability of rRNA synthesis factors in trans. Surprisingly, some lncRNA transcripts can directly originate from nucleolar loci and function in cis. The nucleolar intergenic spacer (IGS), for example, encodes nucleolar transcripts that counteract spurious rRNA synthesis in unperturbed cells. In response to DNA damage, RNAPII-dependent lncRNA originates directly at broken ribosomal (r)DNA loci and is processed into small ncRNA, possibly to modulate DNA repair. Thus, lncRNA-mediated regulation of nucleolar biology occurs by several modes of action and is more direct than anticipated, pointing to an intimate crosstalk of RNA metabolic events.

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Ubiquitin and Ubiquitin-Like Proteins and Domains in Ribosome Production and Function: Chance or Necessity?

International Journal of Molecular Sciences ◽

10.3390/ijms22094359 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4359

Author(s):

Sara Martín-Villanueva ◽

Gabriel Gutiérrez ◽

Dieter Kressler ◽

Jesús de la Cruz

Keyword(s):

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Ribosome Assembly ◽

Cellular Processes ◽

Substrate Protein ◽

Precursor Proteins ◽

Assembly Factors ◽

Ubiquitin Moiety ◽

And Function

Ubiquitin is a small protein that is highly conserved throughout eukaryotes. It operates as a reversible post-translational modifier through a process known as ubiquitination, which involves the addition of one or several ubiquitin moieties to a substrate protein. These modifications mark proteins for proteasome-dependent degradation or alter their localization or activity in a variety of cellular processes. In most eukaryotes, ubiquitin is generated by the proteolytic cleavage of precursor proteins in which it is fused either to itself, constituting a polyubiquitin precursor, or as a single N-terminal moiety to ribosomal proteins, which are practically invariably eL40 and eS31. Herein, we summarize the contribution of the ubiquitin moiety within precursors of ribosomal proteins to ribosome biogenesis and function and discuss the biological relevance of having maintained the explicit fusion to eL40 and eS31 during evolution. There are other ubiquitin-like proteins, which also work as post-translational modifiers, among them the small ubiquitin-like modifier (SUMO). Both ubiquitin and SUMO are able to modify ribosome assembly factors and ribosomal proteins to regulate ribosome biogenesis and function. Strikingly, ubiquitin-like domains are also found within two ribosome assembly factors; hence, the functional role of these proteins will also be highlighted.

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Expanding Role of Ubiquitin in Translational Control

International Journal of Molecular Sciences ◽

10.3390/ijms21031151 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1151 ◽

Cited By ~ 3

Author(s):

Shannon E. Dougherty ◽

Austin O. Maduka ◽

Toshifumi Inada ◽

Gustavo M. Silva

Keyword(s):

Translational Control ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Rna Binding ◽

Protein Quality ◽

Rna Binding Proteins ◽

Ubiquitin Chain ◽

Molecular Aspects ◽

And Function

The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation.

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Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth

Nature Communications ◽

10.1038/s41467-019-13465-y ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Jennifer E. Cowan ◽

Justin Malin ◽

Yongge Zhao ◽

Mina O. Seedhom ◽

Christelle Harly ◽

...

Keyword(s):

Epithelial Cells ◽

T Cell Development ◽

Thymic Epithelial Cells ◽

Fetal Life ◽

Ribosomal Biogenesis ◽

Transcriptional Program ◽

Fetal Thymus ◽

Thymus Development ◽

And Function ◽

Thymus Size

AbstractInteractions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Here we identify distinct transcriptional programs of TEC that account for their age-specific properties, including proliferation rates, engraftability and function. Further analyses identify Myc as a regulator of fetal thymus development to support the rapid increase of thymus size during fetal life. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; meanwhile, inducible expression of Myc in adult TEC similarly promotes thymic growth. Mechanistically, this Myc function is associated with enhanced ribosomal biogenesis in TEC. Our study thus identifies age-specific transcriptional programs in TEC, and establishes that Myc controls thymus size.

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Functional ribosome biogenesis is a prerequisite for p53 destabilization: impact of chemotherapy on nucleolar functions and RNA metabolism

Biological Chemistry ◽

10.1515/hsz-2013-0153 ◽

2013 ◽

Vol 394 (9) ◽

pp. 1133-1143 ◽

Cited By ~ 17

Author(s):

Kaspar Burger ◽

Dirk Eick

Keyword(s):

Ribosomal Rna ◽

Ribosome Biogenesis ◽

Rna Metabolism ◽

Chemotherapeutic Drugs ◽

Tumor Suppressor P53 ◽

Nucleolar Structure ◽

Highly Sensitive ◽

Important Regulator ◽

Sensitive Sensor ◽

And Function

Abstract The production and processing of ribosomal RNA is a complex and well-coordinated nucleolar process for ribosome biogenesis. Progress in understanding nucleolar structure and function has lead to the unexpected discovery of the nucleolus as a highly sensitive sensor of cellular stress and an important regulator of the tumor suppressor p53. Inhibition of ribosomal RNA metabolism has been shown to activate a signaling pathway for p53 induction. This review elucidates the potential of classical and recently developed chemotherapeutic drugs to stabilize p53 by inhibiting nucleolar functions.

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The Impact of KLF2 Modulation on the Transcriptional Program and Function of CD8 T Cells

PLoS ONE ◽

10.1371/journal.pone.0077537 ◽

2013 ◽

Vol 8 (10) ◽

pp. e77537 ◽

Cited By ~ 14

Author(s):

Gavin C. Preston ◽

Carmen Feijoo-Carnero ◽

Nick Schurch ◽

Victoria H. Cowling ◽

Doreen A. Cantrell

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Transcriptional Program ◽

And Function ◽

The Impact

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Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function

Growth Factors ◽

10.1080/08977190701779101 ◽

2007 ◽

Vol 25 (4) ◽

pp. 209-226 ◽

Cited By ~ 155

Author(s):

Katarzyna Jastrzebski ◽

Katherine M. Hannan ◽

Elissaveta B. Tchoubrieva ◽

Ross D. Hannan ◽

Richard B. Pearson

Keyword(s):

Ribosomal Protein ◽

Ribosome Biogenesis ◽

S6 Kinase ◽

Coordinate Regulation ◽

Ribosomal Protein S6 ◽

And Function ◽

Kinase A ◽

Ribosomal Protein S6 Kinase

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Structure and function of ribosomal RNA gene chromatin

Biochemical Society Transactions ◽

10.1042/bst0360619 ◽

2008 ◽

Vol 36 (4) ◽

pp. 619-624 ◽

Cited By ~ 40

Author(s):

Joanna L. Birch ◽

Joost C.B.M. Zomerdijk

Keyword(s):

Ribosomal Rna ◽

Ribosome Biogenesis ◽

Rna Polymerase I ◽

Rrna Genes ◽

Rrna Gene ◽

Pol I ◽

And Function ◽

Polymerase I ◽

Cell Growth And Proliferation ◽

Cellular Control

Transcription of the major ribosomal RNAs by Pol I (RNA polymerase I) is a key determinant of ribosome biogenesis, driving cell growth and proliferation in eukaryotes. Hundreds of copies of rRNA genes are present in each cell, and there is evidence that the cellular control of Pol I transcription involves adjustments to the number of rRNA genes actively engaged in transcription, as well as to the rate of transcription from each active gene. Chromatin structure is inextricably linked to rRNA gene activity, and the present review highlights recent advances in this area.

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Novel Insight Into the Development and Function of Hypopharyngeal Glands in Honey Bees

Frontiers in Physiology ◽

10.3389/fphys.2020.615830 ◽

2021 ◽

Vol 11 ◽

Author(s):

Saboor Ahmad ◽

Shahmshad Ahmed Khan ◽

Khalid Ali Khan ◽

Jianke Li

Keyword(s):

Honey Bees ◽

Future Research ◽

Factors Affecting ◽

Hypopharyngeal Glands ◽

And Function ◽

First Time ◽

The Brain ◽

Insight Into ◽

Made In

Hypopharyngeal glands (HGs) are the most important organ of hymenopterans which play critical roles for the insect physiology. In honey bees, HGs are paired structures located bilaterally in the head, in front of the brain between compound eyes. Each gland is composed of thousands of secretory units connecting to secretory duct in worker bees. To better understand the recent progress made in understanding the structure and function of these glands, we here review the ontogeny of HGs, and the factors affecting the morphology, physiology, and molecular basis of the functionality of the glands. We also review the morphogenesis of HGs in the pupal and adult stages, and the secretory role of the glands across the ages for the first time. Furthermore, recent transcriptome, proteome, and phosphoproteome analyses have elucidated the potential mechanisms driving the HGs development and functionality. This adds a comprehensive novel knowledge of the development and physiology of HGs in honey bees over time, which may be helpful for future research investigations.

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DWV 3C protease uncovers the diverse catalytic triad in insect RNA viruses

10.1101/2022.01.06.475182 ◽

2022 ◽

Author(s):

Xuye Yuan ◽

Tatsuhiko Kadowaki

Keyword(s):

Honey Bees ◽

Rna Viruses ◽

Catalytic Triad ◽

Enzymatic Properties ◽

Host Cells ◽

Deformed Wing Virus ◽

Mutant Proteins ◽

3C Protease ◽

Infected Cells ◽

And Function

Deformed wing virus (DWV) is the most prevalent Iflavirus that is infecting honey bees worldwide. However, the mechanisms of its infection and replication in host cells are poorly understood. In this study, we analyzed the structure and function of DWV 3C protease (3Cpro), which is necessary for the cleavage of the polyprotein to synthesize mature viral proteins. We found that the 3Cpros of DWV and picornaviruses share common enzymatic properties, including sensitivity to the same inhibitors, such as rupintrivir. The predicted structure of DWV 3Cpro by AlphaFold2, the predicted rupintrivir binding domain, and the protease activities of mutant proteins revealed that it has a Cys-His-Asn catalytic triad. Moreover, 3Cpros of other Iflaviruses and Dicistrovirus appear to contain Asn, Ser, Asp, or Glu as the third residue of the catalytic triad, suggesting diversity in insect RNA viruses. Both precursor 3Cpro with RNA-dependent RNA polymerase and mature 3Cpro are present in DWV-infected cells, suggesting that they may have different enzymatic properties and functions. DWV 3Cpro is the first 3Cpro characterized among insect RNA viruses, and our study uncovered both the common and unique characteristics among 3Cpros of Picornavirales. Furthermore, the specific inhibitors of DWV 3Cpro could be used to control DWV infection in honey bees.

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