ResearchPad - microreview https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[A multifunctional small RNA binding protein for sensing and signaling cell envelope precursor availability in bacteria]]> https://www.researchpad.co/article/N33ff824c-2a8c-406a-b01f-54ef06db7cf6 Synthesis of glucosamine-6-phosphate (GlcN6P) by the enzyme GlmS initiates bacterial cell envelope biosynthesis. To ensure ongoing synthesis, GlcN6P homeostasis is required. Escherichia coli achieves this through a post-transcriptional control mechanism comprising the RNA-binding protein RapZ and small RNAs (sRNAs) GlmY and GlmZ. GlmZ stimulates glmS translation by base-pairing. When GlcN6P is abundant, GlmZ is cleaved and inactivated by endoribonuclease RNase E. Cleavage depends on RapZ, which binds GlmZ and recruits RNase E. Decreasing GlcN6P concentrations provoke up-regulation of the decoy sRNA GlmY which sequesters RapZ, thereby suppressing GlmZ decay. In our current study we identify RapZ as the GlcN6P sensor. GlcN6P-free RapZ interacts with and stimulates phosphorylation of the two-component system (TCS) QseE/QseF triggering glmY expression. Thereby generated GlmY sequesters RapZ into stable complexes, allowing for glmS expression. Sequestration by GlmY also disables RapZ to stimulate QseE/QseF, providing a negative feed-back loop limiting the response. When GlcN6P is replenished, GlmY is released from RapZ and rapidly degraded. Our work has revealed a complex regulatory scenario, in which an RNA binding protein senses a metabolite and communicates with two sRNAs, a TCS and ribonuclease RNase E to achieve metabolite homeostasis.

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<![CDATA[Biomechanical stress provides a second hit in the establishment of BMP/TGFβ-related vascular disorders]]> https://www.researchpad.co/article/Na3e7c829-f227-461b-a5f9-bd4b92a2bcad

Cardiovascular disorders are still the leading cause for mortality in the western world and challenge economies with steadily increasing healthcare costs. Understanding the precise molecular pathomechanisms behind and identifying players involved in the early onset of cardiovascular diseases remains crucial for the development of new therapeutic strategies. Taking advantage of CRISPR/Cas9 gene editing in human endothelial cells (ECs), we re-investigated the early molecular steps in a genetic vascular disorder termed pulmonary arterial hypertension (PAH) in our recent study (Hiepen C., Jatzlau J. et al.; PLOS Biol, 2019). Here, mutations in the Bone Morphogenetic Protein type II receptor (BMPR2) prime for the hereditary form (HPAH) with downregulated BMPR2 followed by a characteristic change in SMAD signaling, i.e. gain in both SMAD1/5 and SMAD2/3 responses. Remarkably these cells show increased susceptibility to signaling by TGFβ due to remodeling of the extracellular matrix (ECM) and increased biomechanics acting as a secondary stressor for ECs pathobiology. This clearly places BMPR2 not only as a BMP-signaling receptor, but also as a gatekeeper to protect ECs from excess TGFβ signaling.

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<![CDATA[Plasmodium vivax Reticulocyte Binding Proteins for invasion into reticulocytes]]> https://www.researchpad.co/article/Nd1cd481e-ca9d-43dd-a666-10e9e4279c9c

Abstract

Plasmodium vivax is responsible for most of the malaria infections outside Africa and is currently the predominant malaria parasite in countries under elimination programs. P. vivax preferentially enters young red cells called reticulocytes. Advances in understanding the molecular and cellular mechanisms of entry are hampered by the inability to grow large numbers of P. vivax parasites in a long‐term in vitro culture. Recent progress in understanding the biology of the P. vivax Reticulocyte Binding Protein (PvRBPs) family of invasion ligands has led to the identification of a new invasion pathway into reticulocytes, an understanding of their structural architecture and PvRBPs as targets of the protective immune response to P. vivax infection. This review summarises current knowledge on the role of reticulocytes in P. vivax infection, the function of the PvRBP family of proteins in generating an immune response in human populations, and the characterization of anti‐PvRBP antibodies in blocking parasite invasion.

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<![CDATA[New insights in the mode of action of anti-leishmanial drugs by using chemical mutagenesis screens coupled to next-generation sequencing]]> https://www.researchpad.co/article/N4c5df557-4235-4808-9c50-2780973e3bae

Leishmania parasites are responsible for a range of clinical manifestations ranging from self-resolving cutaneous sores to life-threatening diseases. The management of leishmaniasis is complicated in part by the scarcity of treatment options but also by the emerging or established resistance to available drugs. A major driver of resistance in Leishmania is the amplification of resistance genes taking advantage of the highly repetitive genomic landscape of the parasite. The recent advent of whole genome gain of function screens gave new momentum to the study of such resistance mechanisms, leading to the identification of novel resistance factors and drug targets against approved drugs, which include antimony (SbIII), miltefosine (MIL), paromomycin (PMM), and amphotericin B. However, these screens do not pinpoint single nucleotide variations (SNVs), an important contributor of drug resistance. To fill the gap, our recent study describes the optimization of chemical mutagenesis coupled to next generation sequencing, an approach called Mut-seq, as a way to explore networks of drug resistance genes in organisms with a diploid to mosaic aneuploid genome like Leishmania. Our Mut-seq screen revealed associations between genes linked with lipid metabolism and resistance to MIL, and highlighted the role of a protein kinase in translation leading to resistance to PMM.

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<![CDATA[Monoderm bacteria: the new frontier for type IV pilus biology]]> https://www.researchpad.co/article/N2c869064-8a5a-4990-ada3-b34e88c0b505

Summary

In the diverse world of bacterial pili, type IV pili (Tfp) are unique for two reasons: their multifunctionality and ubiquity. This latter feature offers an extraordinary possibility, that is, to perform comparative studies in evolutionarily distant species in order to improve our fragmentary understanding of Tfp biology. Regrettably, such potential has remained largely untapped, because, for 20 years, Tfp have only been characterised in diderm bacteria. However, recent studies of Tfp in monoderms have started closing the gap, revealing many interesting commonalities and a few significant differences, extending the frontiers of knowledge of Tfp biology. Here, I review the current state of the art of the Tfp field in monoderm bacteria and discuss resulting implications for our general understanding of the assembly and function of these widespread filamentous nanomachines.

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<![CDATA[The pathogenic actinobacterium Rhodococcus equi: what's in a name?]]> https://www.researchpad.co/article/N9313c8f3-8dd0-4fca-8333-6625f6d33972

Summary

Rhodococcus equi is the only recognized animal pathogenic species within an extended genus of metabolically versatile Actinobacteria of considerable biotechnological interest. Best known as a horse pathogen, R. equi is commonly isolated from other animal species, particularly pigs and ruminants, and causes severe opportunistic infections in people. As typical in the rhodococci, R. equi niche specialization is extrachromosomally determined, via a conjugative virulence plasmid that promotes intramacrophage survival. Progress in the molecular understanding of R. equi and its recent rise as a novel paradigm of multihost adaptation has been accompanied by an unusual nomenclatural instability, with a confusing succession of names: "Prescottia equi", "Prescotella equi", Corynebacterium hoagii and Rhodococcus hoagii. This article reviews current advances in the genomics, biology and virulence of this pathogenic actinobacterium with a unique mechanism of plasmid‐transferable animal host tropism. It also discusses the taxonomic and nomenclatural issues around R. equi in the light of recent phylogenomic evidence that confirms its membership as a bona fide Rhodococcus.

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<![CDATA[Shedding light on a Group IV (ECF11) alternative σ factor]]> https://www.researchpad.co/article/N8e21d075-021a-4e7e-a594-75e2ec657123

Summary

This year marks the 50th anniversary of the discovery of σ70 as a protein factor that was needed for bacterial RNA polymerase to accurately transcribe a promoter in vitro. It was 25 years later that the Group IV alternative σs were described as a distinct family of proteins related to σ70. In the intervening time, there has been an ever‐growing list of Group IV σs, numbers of genes they transcribe, insight into the diverse suite of processes they control, and appreciation for their impact on bacterial lifestyles. This work summarizes knowledge of the Rhodobacter sphaeroides σE‐ChrR pair, a member of the ECF11 subfamily of Group IV alternative σs, in protecting cells from the reactive oxygen species, singlet oxygen. It describes lessons learned from analyzing ChrR, a zinc‐dependent anti‐σ factor, that are generally applicable to Group IV σs and relevant to the response to single oxygen. This MicroReview also illustrates insights into stress responses in this and other bacteria that have been acquired by analyzing or modeling the activity of the σE‐ChrR across the bacterial phylogeny.

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<![CDATA[Small mobile sequences in bacteria display diverse structure/function motifs]]> https://www.researchpad.co/article/5b7d9f5c463d7e3388d3772a

Small repeat sequences in bacterial genomes, which represent non-autonomous mobile elements, have close similarities to archaeon and eukaryotic miniature inverted repeat transposable elements. These repeat elements are found in both intergenic and intragenic chromosomal regions, and contain an array of diverse motifs. These can include DNA sequences containing an integration host factor binding site and a proposed DNA methyltransferase recognition site, transcribed RNA secondary structural motifs, which are involved in mRNA regulation, and translated open reading frames found fused to other open reading frames. Some bacterial mobile element fusions are in evolutionarily conserved protein and RNA genes. Others might represent or lead to creation of new protein genes. Here we review the remarkable properties of these small bacterial mobile elements in the context of possible beneficial roles resulting from random insertions into the genome.

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