scholarly journals Isoleucine 44 Hydrophobic Patch Controls Toxicity of Unanchored, Linear Ubiquitin Chains through NF-κB Signaling

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1519 ◽  
Author(s):  
Jessica R. Blount ◽  
Kozeta Libohova ◽  
Gustavo M. Silva ◽  
Sokol V. Todi
Keyword(s):  
Drosophila Melanogaster ◽  
Fruit Fly ◽  
Post Translational Modification ◽  
Ubiquitin Chain ◽  
Interaction Site ◽  
Cellular Processes ◽  
Protein Adduct ◽  
Linear Chains ◽  
Linear Poly ◽  
Free Ubiquitin

Ubiquitination is a post-translational modification that regulates cellular processes by altering the interactions of proteins to which ubiquitin, a small protein adduct, is conjugated. Ubiquitination yields various products, including mono- and poly-ubiquitinated substrates, as well as unanchored poly-ubiquitin chains whose accumulation is considered toxic. We previously showed that transgenic, unanchored poly-ubiquitin is not problematic in Drosophila melanogaster. In the fruit fly, free chains exist in various lengths and topologies and are degraded by the proteasome; they are also conjugated onto other proteins as one unit, eliminating them from the free ubiquitin chain pool. Here, to further explore the notion of unanchored chain toxicity, we examined when free poly-ubiquitin might become problematic. We found that unanchored chains can be highly toxic if they resemble linear poly-ubiquitin that cannot be modified into other topologies. These species upregulate NF-κB signaling, and modulation of the levels of NF-κB components reduces toxicity. In additional studies, we show that toxicity from untethered, linear chains is regulated by isoleucine 44, which anchors a key interaction site for ubiquitin. We conclude that free ubiquitin chains can be toxic, but only in uncommon circumstances, such as when the ability of cells to modify and regulate them is markedly restricted.

scholarly journals piRNA pathway is not required for antiviral defense in Drosophila melanogaster

2016 ◽  
Vol 113 (29) ◽  
pp. E4218-E4227 ◽  
Author(s):  
Marine Petit ◽  
Vanesa Mongelli ◽  
Lionel Frangeul ◽  
Hervé Blanc ◽  
Francis Jiggins ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Germ Line ◽  
Fruit Fly ◽  
Antiviral Response ◽  
Antiviral Defense ◽  
Wild Type ◽  
Cellular Processes ◽  
Pirna Pathway ◽  
Interfering Rna ◽  
Sirna Pathway

Since its discovery, RNA interference has been identified as involved in many different cellular processes, and as a natural antiviral response in plants, nematodes, and insects. In insects, the small interfering RNA (siRNA) pathway is the major antiviral response. In recent years, the Piwi-interacting RNA (piRNA) pathway also has been implicated in antiviral defense in mosquitoes infected with arboviruses. Using Drosophila melanogaster and an array of viruses that infect the fruit fly acutely or persistently or are vertically transmitted through the germ line, we investigated in detail the extent to which the piRNA pathway contributes to antiviral defense in adult flies. Following virus infection, the survival and viral titers of Piwi, Aubergine, Argonaute-3, and Zucchini mutant flies were similar to those of wild type flies. Using next-generation sequencing of small RNAs from wild type and siRNA mutant flies, we showed that no viral-derived piRNAs were produced in fruit flies during different types of viral infection. Our study provides the first evidence, to our knowledge, that the piRNA pathway does not play a major role in antiviral defense in adult Drosophila and demonstrates that viral-derived piRNA production depends on the biology of the host–virus combination rather than being part of a general antiviral process in insects.

scholarly journals The Met1-linked ubiquitin machinery in inflammation and infection

2021 ◽  
Vol 28 (2) ◽  
pp. 557-569
Author(s):  
Berthe Katrine Fiil ◽  
Mads Gyrd-Hansen
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Post Translational Modification ◽  
Ubiquitin Chain ◽  
Cellular Processes ◽  
Polymeric Chains ◽  
Cellular Machinery ◽  
Pleiotropic Functions ◽  
Interferon Responses

AbstractUbiquitination is an essential post-translational modification that regulates most cellular processes. The assembly of ubiquitin into polymeric chains by E3 ubiquitin ligases underlies the pleiotropic functions ubiquitin chains regulate. Ubiquitin chains assembled via the N-terminal methionine, termed Met1-linked ubiquitin chains or linear ubiquitin chains, have emerged as essential signalling scaffolds that regulate pro-inflammatory responses, anti-viral interferon responses, cell death and xenophagy of bacterial pathogens downstream of innate immune receptors. Met1-linked ubiquitin chains are exclusively assembled by the linear ubiquitin chain assembly complex, LUBAC, and are disassembled by the deubiquitinases OTULIN and CYLD. Genetic defects that perturb the regulation of Met1-linked ubiquitin chains causes severe immune-related disorders, illustrating their potent signalling capacity. Here, we review the current knowledge about the cellular machinery that conjugates, recognises, and disassembles Met1-linked ubiquitin chains, and discuss the function of this unique posttranslational modification in regulating inflammation, cell death and immunity to pathogens.

scholarly journals Hox dosage contributes to flight appendage morphology in Drosophila

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rachel Paul ◽  
Guillaume Giraud ◽  
Katrin Domsch ◽  
Marilyne Duffraisse ◽  
Frédéric Marmigère ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Differential Expression ◽  
Hox Genes ◽  
Expression Profiles ◽  
Fruit Fly ◽  
Insect Species ◽  
Wing Morphology ◽  
Hox Proteins ◽  
Spatial Expression ◽  
Flying Insects

AbstractFlying insects have invaded all the aerial space on Earth and this astonishing radiation could not have been possible without a remarkable morphological diversification of their flight appendages. Here, we show that characteristic spatial expression profiles and levels of the Hox genes Antennapedia (Antp) and Ultrabithorax (Ubx) underlie the formation of two different flight organs in the fruit fly Drosophila melanogaster. We further demonstrate that flight appendage morphology is dependent on specific Hox doses. Interestingly, we find that wing morphology from evolutionary distant four-winged insect species is also associated with a differential expression of Antp and Ubx. We propose that variation in the spatial expression profile and dosage of Hox proteins is a major determinant of flight appendage diversification in Drosophila and possibly in other insect species during evolution.

scholarly journals Quantitative investigation reveals distinct phases in Drosophila sleep

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Xiaochan Xu ◽  
Wei Yang ◽  
Binghui Tian ◽  
Xiuwen Sui ◽  
Weilai Chi ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
General Pattern ◽  
Model Organism ◽  
Infrared Camera ◽  
Fruit Fly ◽  
Genetic Dissection ◽  
Power Law Distribution ◽  
Quantitative Investigation ◽  
Waking Up ◽  
Set Up

AbstractThe fruit fly, Drosophila melanogaster, has been used as a model organism for the molecular and genetic dissection of sleeping behaviors. However, most previous studies were based on qualitative or semi-quantitative characterizations. Here we quantified sleep in flies. We set up an assay to continuously track the activity of flies using infrared camera, which monitored the movement of tens of flies simultaneously with high spatial and temporal resolution. We obtained accurate statistics regarding the rest and sleep patterns of single flies. Analysis of our data has revealed a general pattern of rest and sleep: the rest statistics obeyed a power law distribution and the sleep statistics obeyed an exponential distribution. Thus, a resting fly would start to move again with a probability that decreased with the time it has rested, whereas a sleeping fly would wake up with a probability independent of how long it had slept. Resting transits to sleeping at time scales of minutes. Our method allows quantitative investigations of resting and sleeping behaviors and our results provide insights for mechanisms of falling into and waking up from sleep.

scholarly journals The trithorax Group Genemoira Encodes a Brahma-Associated Putative Chromatin-Remodeling Factor in Drosophila melanogaster

1999 ◽  
Vol 19 (2) ◽  
pp. 1159-1170 ◽  
Author(s):  
Madeline A. Crosby ◽  
Chaya Miller ◽  
, Tamar Alon ◽  
Kellie L. Watson ◽  
C. Peter Verrijzer ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Chromatin Remodeling ◽  
Leucine Zipper ◽  
Genetic Relationships ◽  
Fruit Fly ◽  
Protein Product ◽  
Homeotic Genes ◽  
Trithorax Group ◽  
Functional Relationships

ABSTRACT The genes of the trithorax group (trxG) inDrosophila melanogaster are required to maintain the pattern of homeotic gene expression that is established early in embryogenesis by the transient expression of the segmentation genes. The precise role of each of the diverse trxG members and the functional relationships among them are not well understood. Here, we report on the isolation of the trxG gene moira(mor) and its molecular characterization. morencodes a fruit fly homolog of the human and yeast chromatin-remodeling factors BAF170, BAF155, and SWI3. mor is widely expressed throughout development, and its 170-kDa protein product is present in many embryonic tissues. In vitro, MOR can bind to itself and it interacts with Brahma (BRM), an SWI2-SNF2 homolog, with which it is associated in embryonic nuclear extracts. The leucine zipper motif of MOR is likely to participate in self-oligomerization; the equally conserved SANT domain, for which no function is known, may be required for optimal binding to BRM. MOR thus joins BRM and Snf5-related 1 (SNR1), two known Drosophila SWI-SNF subunits that act as positive regulators of the homeotic genes. These observations provide a molecular explanation for the phenotypic and genetic relationships among several of the trxG genes by suggesting that they encode evolutionarily conserved components of a chromatin-remodeling complex.

Semisynthetic triazoles as an approach in the discovery of Novel Lead Compounds

2021 ◽  
Vol 25 ◽  
Author(s):  
Pedro Alves Bezerra Morais ◽  
Carla Santana Francisco ◽  
Heberth de Paula ◽  
Rayssa Ribeiro ◽  
Mariana Alves Eloy ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Modern Drug ◽  
New Chemical Entities ◽  
Almost All ◽  
The 19Th Century

: Historically, the medicinal chemistry is concerned with the approach of organic chemistry to new drug synthesis. Considering the fruitful collections of new molecular entities, the dedicated efforts for medicinal chemistry are rewarding. Planning and search of new and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since the 19th century, notoriously the application of isolated and characterized plant-derived compounds in modern drug discovery and in various stages of clinical development highlight its viability and significance. Natural products influence a broad range of biological processes, covering transcription, translation, and post-translational modification and being effective modulators of almost all basic cellular processes. The research of new chemical entities through “click chemistry” continuously opens up a map for the remarkable exploration of chemical space in towards leading natural products optimization by structure-activity relationship. Finally, here in this review, we expect to gather a broad knowledge involving triazolic natural products derivatives, synthetic routes, structures, and their biological activities.

scholarly journals The split protein phosphatase system

2018 ◽  
Vol 475 (23) ◽  
pp. 3707-3723 ◽  
Author(s):  
Anne Bertolotti
Keyword(s):  
Protein Phosphatase ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Post Translational Modification ◽  
Antagonistic Action ◽  
Cellular Processes ◽  
Depth Study ◽  
Split Protein ◽  
Phosphatase System ◽  
Physiological Substrates

Reversible phosphorylation of proteins is a post-translational modification that regulates all aspect of life through the antagonistic action of kinases and phosphatases. Protein kinases are well characterized, but protein phosphatases have been relatively neglected. Protein phosphatase 1 (PP1) catalyzes the dephosphorylation of a major fraction of phospho-serines and phospho-threonines in cells and thereby controls a broad range of cellular processes. In this review, I will discuss how phosphatases were discovered, how the view that they were unselective emerged and how recent findings have revealed their exquisite selectivity. Unlike kinases, PP1 phosphatases are obligatory heteromers composed of a catalytic subunit bound to one (or two) non-catalytic subunit(s). Based on an in-depth study of two holophosphatases, I propose the following: selective dephosphorylation depends on the assembly of two components, the catalytic subunit and the non-catalytic subunit, which serves as a high-affinity substrate receptor. Because functional complementation of the two modules is required to produce a selective holophosphatase, one can consider that they are split enzymes. The non-catalytic subunit was often referred to as a regulatory subunit, but it is, in fact, an essential component of the holoenzyme. In this model, a phosphatase and its array of mostly orphan substrate receptors constitute the split protein phosphatase system. The set of potentially generalizable principles outlined in this review may facilitate the study of these poorly understood enzymes and the identification of their physiological substrates.

Locomotion is not influenced by denticle number in larvae of the fruit fly Drosophila melanogaster

2005 ◽  
Vol 83 (2) ◽  
pp. 368-371 ◽  
Author(s):  
Mark J Fitzpatrick ◽  
Evelyn Szewczyk
Keyword(s):  
Drosophila Melanogaster ◽  
Related Species ◽  
Natural Variation ◽  
Fruit Fly ◽  
Fruit Flies ◽  
Negative Effects ◽  
Closely Related Species ◽  
Locomotory Performance ◽  
Locomotion Speed

Denticles are small projections on the underside of larval fruit flies that are used to grip the substrate while crawling. Previous studies have shown that (i) there is natural variation in denticle number and pattern between Drosophila melanogaster (Meigen, 1830) and several closely related species and (ii) mutations affecting denticle morphology have negative effects on locomotory performance. We hypothesized that there would be a correlation between denticle number and locomotory performance within populations of D. melanogaster. Despite finding considerable variation in denticle number, we found no correlation between denticle number and three measurements of larval locomotion: speed, acceleration, and absolute turning rate.

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