scholarly journals Modeling slow-processing of toxin messenger RNAs in type-I Toxin-Antitoxin systems: post-segregational killing and noise filtering

2018 ◽  
Author(s):  
Yusuke Himeoka ◽  
Namiko Mitarai
Keyword(s):  
Small Rnas ◽  
Present Model ◽  
Regulatory Mechanism ◽  
Type I ◽  
Messenger Rnas ◽  
Ribosome Binding ◽  
Plasmid Loss ◽  
Zero Number ◽  
Growth Inhibiting

AbstractIn type-I toxin-antitoxin (TA) systems, the action of growth-inhibiting toxin proteins is counteracted by the antitoxin small RNAs (sRNAs) that prevent the translation of toxin messenger RNAs (mRNAs). When a TA module is encoded on a plasmid, the short lifetime of antitoxin sRNA compared to toxin mRNAs mediates post-segregational killing (PSK) that contribute the plasmid maintenance, while some of the chromosomal encoded TA loci have been reported to contribute to persister formation in response to a specific upstream signal. Some of the well studied type-I TA systems such ashok/sokare known to have a rather complex regulatory mechanism. Transcribed full-length toxin mRNAs fold such that the ribosome binding site is not accessible and hence cannot be translated. The mRNAs are slowly processed by RNases, and the truncated mRNAs can be either translated or bound by antitoxin sRNA to be quickly degraded. We analyze the role of this extra processing by a mathematical model. We first consider the PSK scenario, and demonstrate that the extra processing compatibly ensures the high toxin expression upon complete plasmid loss, without inducing toxin expression upon acquisition of a plasmid or decrease of plasmid number to a non-zero number. We further show that the extra processing help filtering the transcription noise, avoiding random activation of toxins in transcriptionally regulated TA systems as seen in chromosomal ones. The present model highlights impacts of the slow processing reaction, offering insights on why the slow processing reactions are commonly identified in multiple type-I TA systems.

scholarly journals RNA Regulated Toxin-Antitoxin Systems in Pathogenic Bacteria

2021 ◽  
Vol 11 ◽  
Author(s):  
David D. Sarpong ◽  
Erin R. Murphy
Keyword(s):  
Small Rnas ◽  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
Environmental Changes ◽  
Bacterial Toxin ◽  
Type I ◽  
Bacterial Physiology ◽  
Type Iii ◽  
Two Factors

The dynamic host environment presents a significant hurdle that pathogenic bacteria must overcome to survive and cause diseases. Consequently, these organisms have evolved molecular mechanisms to facilitate adaptation to environmental changes within the infected host. Small RNAs (sRNAs) have been implicated as critical regulators of numerous pathways and systems in pathogenic bacteria, including that of bacterial Toxin-Antitoxin (TA) systems. TA systems are typically composed of two factors, a stable toxin, and a labile antitoxin which functions to protect against the potentially deleterious activity of the associated toxin. Of the six classes of bacterial TA systems characterized to date, the toxin component is always a protein. Type I and Type III TA systems are unique in that the antitoxin in these systems is an RNA molecule, whereas the antitoxin in all other TA systems is a protein. Though hotly debated, the involvement of TA systems in bacterial physiology is recognized by several studies, with the Type II TA system being the most extensively studied to date. This review focuses on RNA-regulated TA systems, highlighting the role of Type I and Type III TA systems in several pathogenic bacteria.

scholarly journals RNase III-mediated processing of a trans-acting bacterial sRNA and its cis-encoded antagonist

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Sarah Lauren Svensson ◽  
Cynthia Mira Sharma
Keyword(s):  
Stress Responses ◽  
Small Rnas ◽  
Foodborne Pathogen ◽  
Transcriptional Regulators ◽  
Rrna Processing ◽  
Rnase E ◽  
Rnase Iii ◽  
Ribosome Binding ◽  
Colonization Factor

Bacterial small RNAs (sRNAs) are important post-transcriptional regulators in stress responses and virulence. They can be derived from an expanding list of genomic contexts, such as processing from parental transcripts by RNase E. The role of RNase III in sRNA biogenesis is less well understood despite its well-known roles in rRNA processing, RNA decay, and cleavage of sRNA-mRNA duplexes. Here, we show that RNase III processes a pair of cis-encoded sRNAs (CJnc190 and CJnc180) of the foodborne pathogen Campylobacter jejuni. While CJnc180 processing by RNase III requires CJnc190, In contrast, RNase III processes CJnc190 independent of CJnc180 via cleavage of an intramolecular duplex. We also show that CJnc190 directly represses translation of the colonization factor PtmG by targeting a G-rich ribosome binding site, and uncover that CJnc180 is a cis-acting antagonist of CJnc190, indirectly affecting ptmG regulation. Our study highlights a role for RNase III in sRNA biogenesis and adds cis-encoded RNAs to the expanding diversity of transcripts that antagonize bacterial sRNAs.

scholarly journals Translational regulation by bacterial small RNAs via an unusual Hfq-dependent mechanism

2017 ◽  
Author(s):  
Muhammad S. Azam ◽  
Carin K. Vanderpool
Keyword(s):  
Binding Site ◽  
Small Rnas ◽  
Translational Regulation ◽  
Regulatory Mechanism ◽  
Role Reversal ◽  
Translational Repression ◽  
Ribosome Binding ◽  
Reversal Mechanism ◽  
Direct Regulator ◽  
Dependent Mechanism

ABSTRACTIn bacteria, the canonical mechanism of translational repression by small RNAs (sRNAs) involves sRNA-mRNA base pairing that occludes the ribosome binding site (RBS), directly preventing translation. In this mechanism, the sRNA is the direct regulator, while the RNA chaperone Hfq plays a supporting role by stabilizing the sRNA. There are a few examples where the sRNA does not directly interfere with ribosome binding, yet translation of the target mRNA is still inhibited. Mechanistically, this non-canonical regulation by sRNAs is poorly understood. Our previous work demonstrated repression of the mannose transporter manX mRNA by the sRNA SgrS, but the regulatory mechanism was unknown. Here, we report that manX translation is controlled by a molecular role-reversal mechanism where Hfq, not the sRNA, is the direct repressor. Hfq binding adjacent to the manX RBS is required for sRNA-mediated translational repression. Translation of manX is also regulated by another sRNA, DicF, via the same non-canonical Hfq-dependent mechanism. Our results suggest that the sRNAs recruit Hfq to its binding site or stabilize the mRNA-Hfq complex. This work adds to the growing number of examples of diverse mechanisms of translational regulation by sRNAs in bacteria.

Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice

2000 ◽  
Vol 12 (12) ◽  
pp. 4447-4456 ◽  
Author(s):  
Rose-Marie Bluthe ◽  
Sophie Laye ◽  
Bruno Michaud ◽  
Chantal Combe ◽  
Robert Dantzer ◽  
...  
Keyword(s):  
Tumour Necrosis ◽  
Interleukin 1 ◽  
Tumour Necrosis Factor Alpha ◽  
Type I ◽  
Sickness Behaviour ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

Prospective Memory Development Across the Lifespan

2020 ◽  
Vol 25 (3) ◽  
pp. 162-173 ◽  
Author(s):  
Sascha Zuber ◽  
Matthias Kliegel
Keyword(s):  
Prospective Memory ◽  
Healthy Aging ◽  
Present Model ◽  
Current Knowledge ◽  
Well Being ◽  
The Elderly ◽  
Cognitive Factors ◽  
Everyday Functioning ◽  
Integrative Framework

Abstract. Prospective Memory (PM; i.e., the ability to remember to perform planned tasks) represents a key proxy of healthy aging, as it relates to older adults’ everyday functioning, autonomy, and personal well-being. The current review illustrates how PM performance develops across the lifespan and how multiple cognitive and non-cognitive factors influence this trajectory. Further, a new, integrative framework is presented, detailing how those processes interplay in retrieving and executing delayed intentions. Specifically, while most previous models have focused on memory processes, the present model focuses on the role of executive functioning in PM and its development across the lifespan. Finally, a practical outlook is presented, suggesting how the current knowledge can be applied in geriatrics and geropsychology to promote healthy aging by maintaining prospective abilities in the elderly.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

The Role of Toll-Like Receptors and Type I Interferons in Host Responses to Bacteria

2009 ◽  
Vol 5 (2) ◽  
pp. 143-149
Author(s):  
Marja Ojaniemi ◽  
Mari Liljeroos ◽  
Reetta Vuolteenaho
Keyword(s):  
Type I Interferons ◽  
Host Responses ◽  
Type I ◽  
Toll Like Receptors

scholarly journals Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

2021 ◽  
Vol 13 (1) ◽  
pp. 17-29
Author(s):  
Emann M Rabie ◽  
Sherry X Zhang ◽  
Andreas P Kourouklis ◽  
A Nihan Kilinc ◽  
Allison K Simi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Type I ◽  
Matrix Degradation ◽  
Human Breast ◽  
Rate Of Invasion

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

scholarly journals Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren’s Syndrome

2021 ◽  
Vol 22 (6) ◽  
pp. 3090
Author(s):  
Toshimasa Shimizu ◽  
Hideki Nakamura ◽  
Atsushi Kawakami
Keyword(s):  
Immune Responses ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

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